ES2860850A1 - ANTIVIRAL AGENTS FOR CORONAVIRUS (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Compositions and compounds for the treatment of coronavirus infection, and for the treatment of severe acute respiratory syndrome (SARS) caused by coronavirus. (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

Antiviral Agents for Coronavirus

FIELD OF THE INVENTION

The present invention is within the field of medicine, and relates to compositions and compounds for the treatment of coronavirus infection, and for the treatment of severe acute respiratory syndrome (SARS) caused by coronavirus.

INTRODUCTION

In the 21st century, we have seen coronaviruses emerge in Asia, the East and the West. In 2002/3, severe acute respiratory syndrome (SARS) affected 238 people and killed 33 in Singapore, including healthcare workers. Ten years after that, the Middle East respiratory syndrome coronavirus (MERS or nCoV-2012) emerged in the Middle East and continues to appear with sporadic cases and localized outbreaks, including one in Korea. The outbreak of pneumonia caused by the acute respiratory disease New Coronavirus 2019-nCoV (also named as COVID-19 by the WHO on February 11, 2020) in Wuhan, Hubei province of China, at the end of 2019 is a great challenge for public health and clinical treatment. All of these coronaviruses have had significant human morbidity and mortality. These RNA viruses with crown-shaped spikes on their envelope have been predicted to be emerging pathogens with outbreak potential due to their inherent propensity for rapid mutation and recombination due to their large genomes. Therefore, it is urgent to investigate antiviral drugs that could be useful in treating COVID-19 virus infection.

Substance P (SP) is an undecapeptide (Figure 1) that belongs to the tachykinin family of peptides. It is derived from the pre-protachykinin-A gene and is present in most human organ systems, including the immune system. In the nervous system, SP acts primarily as a neurotransmitter / neuromodulator. The biological actions of tachykinins are mediated by three receptors: neurokinin (NK) -1, NK-2, and NK-3. SP, the natural ligand of the NK-1 receptor (NK-1R), shows the highest affinity for this receptor. The C-terminal sequence of SP is essential for affinity and the minimal SP fragment that retains good affinity for the NK-1R is SP 6-11 (Gln-Phe-Phe-Gly-Leu-Met). Furthermore, like the SP, the Hemokinin-1 undecapeptide (Hemokinin-1, HK-1) has a similar affinity for NK-1R and both peptides have the same C 6-11 terminal (Gln-Phe-Phe-Gly-Leu-Met). SP is involved in inflammation and virus infections. Many studies have confirmed that SP and NK-1R are involved in infection with human immunodeficiency virus (HIV), measles virus, human respiratory syncytial virus (HRSV), encephalomyocarditis virus infection (ECMCV) and Varicella zoster virus (VZV) infection. Furthermore, the presence of a SP homologous peptide domain in the viral binding / entry proteins of HIV, HRSV, MV and EMCV has been reported to be a common feature and this suggests that the viruses mimic the included SP sequences. on viral entry / binding proteins upon entry, via NK-1R, into the host cell. Furthermore, VZV induces nuclear translocation of NK-1R (virus replication), promoting lamellipodia formation and viral spread in spinal astrocytes. The proviral function of nuclear NK-1R associated with the formation of lamellipodia and the spread of VZV suggests that the binding of a putative VZV ligand to NK-1R produces a dramatically different downstream effect of NK-1R than the binding of SP. On the contrary, in a concentration-dependent manner, the aprepitant and rolapitant NK-1R (NK-1RA) antagonists counteract in vitro and in vivo the aforementioned pathophysiological actions mediated by the putative HIV ligand, VZV to NK-1R.

DESCRIPTION OF THE FIGURES OF THE INVENTION

Fig. 1. SP / HK-1 C-terminal sequence. The COVID-19 peaks show the sequence of homologous dipeptides of the surface glycoprotein SP. Sequence of the second extracellular loops. NK-1R seven-domain transmembrane or GP-associated receptor.

Fig. 2 . SP sequence (SEQ ID NO: 3). Surface sequence of COVID-19 virus spike glycoprotein (SEQ ID NO: 4) (in bold, SP homologous dipeptides and tripeptides of amino and carboxy termini).

Fig. 3 . SP sequence (SEQ ID NO: 3). Sequence of phosphoprotein (SEQ ID NO: 5), membrane glycoprotein (SEQ ID NO: 6) and envelope protein (SEQ ID NO: 7) of COVID-19 virus (in bold, homologous SP dipeptides and tripeptides of the amino end and carboxy terminal).

Fig. 4 . SP sequence (SEQ ID NO: 3). ACE2 protein sequence (SEQ ID NO: 8) (in bold, SP homologous dipeptides and tripeptides from amino and carboxy terminus).

DESCRIPTION OF THE INVENTION

The membrane of all coronaviruses is made up of a minimum of three viral proteins: a spike protein, a type of glycoprotein, a membrane protein that spans the membrane, and an envelope protein, a highly hydrophobic protein that covers the entire structure of the coronavirus. .

In the present invention it is shown that the binding of the COVID-19 virus proteins of a putative viral ligand to NK-1R is by mimicking the SP sequences by binding to NK-1R in a similar way to other viruses that mimic the SP sequences by binding. to host NK-1R cells, for virus entry into cells, virus replication, and viral spread. The invention shows the sequences of the COVID-19 virus proteins and the possible homologous SP peptides contained in the COVID-19 virus proteins. A clinical trial is also described where an NK-R1 antagonist is administered for the treatment of COVID-19 infection.

Therefore, a first aspect of the invention refers to a modulating agent of the neurokinase-1 (NK-1R) receptor for the prevention, amelioration and / or treatment of coronavirus infection, and preferably of the Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 or COVID19.

Preferably an NK-R1 receptor antagonist is referred to as antiviral.

Another preferred embodiment relates to a neurokinase-1 (NK-1R) receptor modulating agent for the prevention, amelioration, and / or treatment of severe acute respiratory syndrome (SARS) caused by the coronavirus. Preferably, the modulating agent is a neurokinase-1 receptor (NK-1R) antagonist.

The term "neurokinase-1 receptor", also called NK-1R, TACR1, SPR; NKIR; TAC1R, refers to both the human gene and protein. The gene belongs to a family of tachykinin receptor genes. These receptors Tachykinin are characterized by interactions with G proteins and contain seven hydrophobic transmembrane regions. This gene encodes the receptor for tachykinin substance P, also known as neurokinin 1. The encoded protein is also involved in mediating the phosphatidylinositol metabolism of substance P .

In the context of the present invention, NK-1R is also defined by a nucleotide or polynucleotide sequence, which constitutes the coding sequence for the NK-1R protein, and which would comprise various variants from:

a) nucleic acid molecules encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 1,

b) nucleic acid molecules whose hybrid complementary strand with the polynucleotide sequence of a),

c) nucleic acid molecules whose sequence differs from a) and / or b) due to the degeneracy of the genetic code,

d) nucleic acid molecules that encode a polypeptide comprising the amino acid sequence with an identity of at least 80%, 90%, 95%, 98% or 99% with SEQ ID NO: 1. in the that the polypeptide encoded by said nucleic acids possesses the activity and structural characteristics of the NK-1R protein.

SEQ ID NO: 1

MDNVLPVDSDLSPNISTNTSEPNQFVQPAWQIVLWAAAYTVIWTSWGNVWMWIIL AHKRMRTVTNYFLVNLAFAEASMAAFNTVVNFTYAVHNEWYYGLFYCKFHNFFPIAA VFASIYSMTAVAFDRYMAIIHPLQPRLSATATKVVICVIWVLALLLAFPQGYYSTTETMP SRVVCMIEWPEHPNKIYEKVYHICVTVLIYFLPLLVIGYAYTVVGITLWASEIPGDSSDR YHEQVSAKRKWKMMIWVCTFAICWLPFHIFFLLPYINPDLYLKKFIQQVYLAIMWLAM SSTMYNPIIYCCLNDRFRLGFKHAFRCCPFISAGDYEGLEMKSTRYLQTQGSVYKVSR LETTISTVVGAHEEEPEDGPKATPSSLDLTSNCSSRSDSKTMTESFSFSSNVLS

SEQ ID NO: 2

GAGCTGAGCAACCCGAACCGAGAGGTGCCCGCGAAACTGCAGGCGGCGGCAGC GGCAGCAAAAGAGAAGGAAAAATCTCCAGCTGGATACGAAGCTCCAGAATCCTGG CCATAGGCTCAGAACTTTTACAGGTCGCGCTGCAATGGGCCCCCACTTCGCTCCT AAGTCCTCACGCAGCACAGGGCTTTGCCTTTCCCTGCGGAGGAAGGAGAAATAG GAGTTGCAGGCAGCAGCAGGTGCATAAATGCGGGGGATCTCTTGCTTCCTAGAA CTGTGACCGGTGGAATTTCTTTCCCTTTTTCAGTTTACCGCAAGAGAGATGCTGTC TCCAGACTTCTGAACTCAAACGTCTCCTGAAGCTTGAAAGTGGAGGAATTCAGAG CCACCGCGGGCAGGCGGGCAGTGCATCCAGAAGCGTTTATATTCTGAGCGCCAG TTCAGCTTTCAAAAAGAGTGCTGCCCAGAAAAAGCCTTCCACCCTCCTGTCTGGC TTTAGAAGGACCCTGAGCCCCAGGCGCCAGCCACAGGACTCTGCTGCAGAGGGG GGTTGTGTACAGATAGTAGGGCTTTACCGCCTAGCTTCGAAATGGATAACGTCCT CCCGGTGGACTCAGACCTCTCCCCAAACATCTCCACTAACACCTCGGAACCCAAT CAGTTCGTGCAACCAGCCTGGCAAATTGTCCTTTGGGCAGCTGCCTACACGGTCA TTGTGGTGACCTCTGTGGTGGGCAACGTGGTAGTGATGTGGATCATCTTAGCCCA CAAAAGAATGAGGACAGTGACGAACTATTTTCTGGTGAACCTGGCCTTCGCGGAG GCCTCCATGGCTGCATTCAATACAGTGGTGAACTTCACCTATGCTGTCCACAACG AATGGTACTACGGCCTGTTCTACTGCAAGTTCCACAACTTCTTTCCCATCGCCGCT GTCTTCGCCAGTATCTACTCCATGACGGCTGTGGCCTTTGATAGGTACATGGCCA TCATACATCCCCTCCAGCCCCGGCTGTCAGCCACAGCCACCAAAGTGGTCATCTG TGTCATCTGGGTCCTGGCTCTCCTGCTGGCCTTCCCCCAGGGCTACTACTCAACC ACAGAGACCATGCCCAGCAGAGTCGTGTGCATGATCGAATGGCCAGAGCATCCG AACAAGATTTATGAGAAAGTGTACCACATCTGTGTGACTGTGCTGATCTACTTCCT CCCCCTGCTGGTGATTGGCTATGCATACACCGTAGTGGGAATCACACTATGGGCC AGTGAGATCCCCGGGGACTCCTCTGACCGCTACCACGAGCAAGTCTCTGCCAAG CGCAAGGTGGTCAAAATGATGATTGTCGTGGTGTGCACCTTCGCCATCTGCTGGC TGCCCTTCCACATCTTCTTCCTCCTGCCCTACATCAACCCAGATCTCTA CCTGAAG AAGTTTATCCAGCAGGTCTACCTGGCCATCATGTGGCTGGCCATGAGCTCCACCA TGTACAACCCCATCATCTACTGCTGCCTCAATGACAGGTTCCGTCTGGGCTTCAA GCATGCCTTCCGGTGCTGCCCCTTCATCAGCGCCGGCGACTATGAGGGGCTGGA AATGAAATCCACCCGGTATCTCCAGACCCAGGGCAGTGTGTACAAAGTCAGCCGC CTGGAGACCACCATCTCCACAGTGGTGGGGGCCCACGAGGAGGAGCCAGAGGA CGGCCCCAAGGCCACACCCTCGTCCCTGGACCTGACCTCCAACTGCTCTTCACG AAGTGACTCCAAGACCATGACAGAGAGCTTCAGCTTCTCCTCCAATGTGCTCTCC TAGGCCACAGGGCCTTTGGCAGGTGCAGCCCCCACTGCCTTTGACCTGCCTCCC TTCATGCATGGAAATTCCCTTCATCTGGAACCATCAGAAACACCCTCACACTGGGA CTTGCAAAAAGGGTCAGTATGGGTTAGGGAAAACATTCCATCCTTGAGTCAAAAAA TCTCAATTCTTCCCTATCTTTGCCACCCTCATGCTGTGTGACTCAAACCAAATCACT GAACTTTGCTGAGCCTGTAAAATAAAAGGTCGGACCAGCTTTTCCCAAAAGCCCAT TCATTCCATTCTGGAAGTGACTTTGGCTGCATGCGAGTGCTCATTTCAGGATGAAT TCTGCAGCACAGCTGCGGACCCGGAAGACTCATTTTCCTGGAGCCCCGTGTTACT TCAATAAAGTTATCTCAGATTAGCCTCCTGCAGCTGGAGGCTCCTATCACCCCAG CCTACGCTTGACAGGGTGAACAAAAGAAGGCACCACATAACATCTAAATGAAAAAT TTAGCCCTGTCTTCTAAGCATCTGTGAAAAGAAACATATGTATTCCCCTTTTTGGCA TCTCAGTATTTCAGTACATTTATACATCATGAGATT GAGAACCTCGGGCTTCCACA TTATGTCCCCGGTGACTGTCCTGAGCAGCCGACGCAAGCAGAATATGTCCACTGA TACCTGCTAGTTCTCTTACAGACCAGGAATTGGGAGACTTGCACTACATTTAATGT GTAGTTGACCCTCTTTTCCTACTTGTAAACAAGGGGACTGAACTAGATAATCTAAG TGTTCCTTCGAATCTTAACATCCCGTGGTTCAAGGATTGTATGAGTTTTTTGTTTGT TTTACAAAAAAAAACAAAACGAAGAATAAAAGAATAGAAAAGAATAGGAGCAGTGA GTCTTGTAACTAATACCCAGTTCCTGGAGATGTAGCAACTGCTAAGGCCATCTGTA ACTATCCATCTCAGACATTCTCCGATTTATCTTAAAATCCTGAGTACATTCCTTCTC ATGGAAGGTTTTGGCTTTTGACAGAGCAGAGGACTTCATGCCAAGGCCTGCATCC ATCCAGCTTTAGCAGGCAGAATTTCATAGCTGCAGAACACTGTCAGAGAAGACAA ATGTGGGCTCCCTGCTTTAACCTTTTGGGTATTTTAGGGTGGGGGCCCTAACCTT CATTCTTAGTTTTACACTAGCATCGTGCTCATATGTGCGACAAGCAAGAAGGCTGC ACTTTGCAGCTGCACTTCTGGGAAGAGGGCATCTTGCATCTTCCCTTCAGACTCT CTGAATGTCTCCTCCCTGCTCCATGGCTTTGCCAGCTTCCTGTCTCTAAGGGGTA GAATGACTCATCAACCCTAAAGGACAGTCAGTCTTCCAAGAGCCATGAACTGAAT GCTTTATATCCTAATTTAGATTTAGAGTTTCCAGAAGGTGAGCATGCAGTTTTGTTT TGTTTTTTTTTCTGTCTCCCAAATCTGTGTTTTTTCCAGATATGGCTGGAAGCAGAA GCTTCATGTAACATCCATGAATGTCCTCCTGGTAGTTTGCATAATGGATGCACATG TGCCGCATCCATAACATTAAGGGGAGAATAATGCATGGTTTACAGCCTTTGCCAG CCCTGCTGGCTCTAATTCTACCAGGGCATCCACA GGCCTGGGGGAAGAAGAAAC AGTATAAGCCAGAAAACCTCAAGAACTACATTCTCTAAAGCAGCATGGAAAGTTTT AAATAAACTAAGTGAAGCCAGATCATTGCAGATATATAAATGGAAGACAAAATTTA GAAGCAACAAAAGTTAGTGCCCTAAGCATTAGTCATACTTCCAATAGAGAATCTTG CTGTGTATGGATTACTCACTTTGGAAGAATGTAAAGAGCTAACATGATTATGAGAA GTACCTGAGAAGATGGTGTCAAGAAGTTGGGGACACCCCATCTATGGAAGAGAAG GTTAGAGTTGAGCTCAACGAGGATTAACTGAGTGCCTCCTCTGGACTTTGCCCTG AACTGGGAACACACAGCCCCTGCAGCTCTTGAAGAGCCTACCTTATTGGCCATCA CTAACTAACTCACCAGTCCTAGTGAGTCTAAGCTGCCCAGCAGTCTTGGAGGCAT CTGAGAGGACAGATTCTCCACAGAATTCTAAAAACCCACACTCAACATGGGCAGT CAAGCCAAAGACTGGGACCTTTGGAGAGCCTCTGGAATGAGAGTTCTCTGGGGTA CTTCCAAAGGGAGCTGGCAGTCAGTCCAGGGGACCTAAAGGAATTTGGTTGAACA GTATCATCTCTGTGCATAGTAAGAGGGAATGTTGGGTGGTCCGGGCAGTTTCCAA TATGGCAAAGCATCTGCTTGGACAGTGCCAGCAAGCCTTCCTCTGACCCAGTCTC CAATGTCCACTAACTTATAAAAATGTCATCAACTCCCACATGTAAGAAACACCATG ATTTGTACTGTGCATGGGTCACATTCTTATTCTAGAAATGCATCACCCTGTGTTTAT CCAAGTGTGTTTACTTGGTGTAATGTCCAGTAGTAATAGAATATGAAATATCAAGG AACCATCTTTGTTACGTGACTTCCAAAATGTGAGATCTCATTGCTGTCACTGTGAT ATTTGTATTGTGTGAATC TCTTCCTCCTCTTCCTCCTCATGCTTTCTCAGGGAGGA GCCCTGATGTATATCATGAACTCACAGTTCCTAGACCACAGTAATTGAGGGGCGG TGGGGGGGCCTTTATCGGAGAAGCTAGAGAACAAGAGTCCTTCTCCTCCTTATCC CCCAACAGGACACTAAGAGACAAGGACTGAGTGGAATCCTGGAGAAAGGGGACT CAGGAACTGACCTCATTGGCCTGATTTGTGAGGAGAGGAGTATAAGTGGAGAGG GGCCATTCCTGAGGTTTCCGTGTTTTCCAGCCTGGTCTCCTGGAAAGAATCTTTAT ACAGAAATAAAGTATGTGTTTCACTC

NK-1R activity can be modulated by modifying the levels and / or activity of the NK-1R protein, or by modifying the levels at which the NK-1R gene is transcribed such that the levels of NK-1R protein activity in the cell is modulated. Antagonists are substances that not only do not activate the receptor, but actually block its activation by agonists. In the context of the present invention, inhibition is the preferred form of modulation.

Severe acute respiratory syndrome, also known by its acronym in English SARS ( severe acute respiratory syndrome ), is an atypical pneumonia that first appeared in November 2002 in the province of Guangzhou, China. SARS usually begins with a high fever (a fever greater than 100.4 ° F [> 38.0 ° C]). Other symptoms can be a headache, a general feeling of discomfort, and pain in the body. Some people experience mild respiratory symptoms early in the illness. About 10 to 20 percent of patients suffer from diarrhea. After 2 to 7 days, SARS patients may develop a dry cough. Most patients get pneumonia.

Coronaviruses are organisms of the Superkingdom Virus, order Nidovirales, suborder Cornidovirineae Family Coronaviridae ; Orthocoronavirinae Subfamily; Genus Betacoronavirus ; Subgenus Sarbecovirus; Species Severe acute respiratory syndrome-related coronavirus.

Neurokinase-1 receptor antagonists are known in the state of the art.

Thus, in a preferred embodiment of this aspect of the invention, the modulating agents comprised in the composition of the invention are selected from a list comprising:

a) an organic molecule,

b) an RNA molecule,

c) an antisense oligonucleotide,

d) an antibody, or e) a ribozyme.

Nucleotide sequences specifically complementary to a given DNA or RNA sequence could form complexes and block transcription or translation. Thus, with the progress of post-transcriptional gene silencing, and in particular of interfering RNA (interfering RNA or RNAi), tools have been developed that allow the specific inhibition of gene expression. The inhibition of the expression of the NK-1R protein would therefore constitute the inhibition of its biological activity, and specifically, of the entry of the coronavirus into the cell, its reolication in the nucleus, and its transmission to adjacent cells by the lamellipodia.

By "antisense polynucleotides" we mean chains of ribonucleotides or deoxyribonucleotides that can inhibit the production of NK-1R by one of three mechanisms:

1- Interfering with transcription, when hybridizing in the structural gene or in a regulatory region of the gene that codes for NK-1R. Since transcription or expression is effectively blocked by hybridization of the antisense oligonucleotide with DNA, NK-1R production decreases.

2- The binding of the antisense oligonucleotide in the cytoplasm with the mRNA, interfering with the formation of the translation construction itself, inhibiting the translation of mRNA to the protein.

3- The formation of a duplex antisense mRNA that allows a rapid degradation of the duplex mRNA by RNases (such as RNase H). This results in a lower production of NK-1R.

Antisense oligonucleotides capable of inhibiting NK-1R are known in the state of the art. For example, and without limiting us, it could be a sequence of ribonucleotides or RNA that belongs to the so-called siRNA ( small interfering RNA), small interfering RNA or silencing RNA, capable of inhibiting the genetic expression of NK-1R. In the context of the present specification is defined as "siRNA" (small interíeríng RNA or small interfering RNA) a class of dsRNAs of 19 to 25 nucleotides long, and most preferably between 21 and 23 nucleotides, which is involved in the RNA interference pathway, where siRNA interferes with the expression of a specific gene. In the present invention, this specific gene is NK-1R.

They could also be an RNA construct that at least contains any one of the possible siRNA nucleotide sequences capable of inhibiting the expression of NK-1R, and without prejudice to the fact that they additionally form part of the present invention any of the RNA sequences and constructions of the invention described above that are subject to modifications, preferably chemical ones, that lead to greater stability against the action of ribonucleases and thus to greater efficiency. Without these modifications implying the alteration of its mechanism of action, which is the specific binding to the RISC complex ( RNA-induced silencing complex), activating it and manifesting a helicase activity that separates the two strands, leaving only the antisense strand associated with the complex. The resulting ribonucleoprotein complex binds to the target mRNA (NK-1R messenger RNA, listed in SEQ ID NO: 2). If the complementarity is not perfect, RISC is associated with the messenger and the translation is attenuated. But if it is perfect, RISC acts as RNase, cutting off the messenger and leaving it free to repeat the process.

Additionally, it is clear to a person skilled in the art that a large number of mRNA polynucleotides can be translated into NK-1R as a consequence, for example, that the genetic code is degenerate. Any siRNA capable of inhibiting the translation of these mRNAs are also part of the invention.

The preparation of the siRNA sequence of the invention or the RNA construction of the invention would be obvious to an expert in the field, and could be carried out by chemical synthesis, which also allows the incorporation of chemical modifications both in the different nucleotides of the product such as the incorporation of other chemical compounds at either end. On the other hand, the synthesis could also be carried out enzymatically using any of the available RNA polymerases. The enzymatic synthesis also allows some chemical modification of the inhibitory products or RNAs.

The design of the nucleotide sequence of the siRNA of the invention would also be apparent to a person skilled in the art. Thus, it could be carried out by means of a random design in which 19-25 bases of the target mRNA are selected without taking into account the sequence or positional information that it has in the transcript. Another non-limiting alternative of the present invention would be the conventional design using simple parameters developed by the pioneers of the technique (Calipel, A. et al., 2003. J Biol Chem. 278 (43): 42409-42418) completed with an analysis Nucleotide BLAST. Another possibility could be a rational design, using a computerized procedure aimed at identifying the optimal siRNA targets in an mRNA. The target sequences are analyzed in groups of 19 nucleotides at a time and those with the best characteristics are identified based on an algorithm that incorporates a large number of thermodynamic and sequence parameters.

A DNA genetic construct could also form part of the composition of the invention, which would direct the in vitro or intracellular transcription of the siRNA sequence or RNA construct of the invention, and which comprises at least one of the following types of sequences: a) DNA nucleotide sequence, preferably double-stranded, comprising at least the coding sequence of the siRNA of the invention or of the RNA construct of the invention for its transcription, or, b) nucleotide sequence of DNA, preferably double-stranded, corresponding to a gene expression vector or system that comprises the coding sequence of the RNA sequence of the invention operatively linked with at least one promoter that directs the transcription of said nucleotide sequence of interest, and with other sequences necessary or appropriate for transcription and their adequate regulation in time and place, for example, start and stop signals, sites of cut, polyadenylation signal, origin of replication, transcriptional activators (i enhancers ), transcriptional silencers ( silencers), etc. .. for use in those pathological contexts in which NK-1R is contributing to the worsening of coronavirus infection and / or the appearance of SARS. Multiple of these constructs, systems or expression vectors can be obtained by conventional methods known to those skilled in the art (Sambrook et al. 2001. Molecular Cloning: A Laboratory Manual. CoId Spring Harbor Laboratory Press, New York)

The compositions of the present invention allow the transfection of the siRNA of the invention into a cell, in vivo or in vitro. Transfection could be carried out, but not limited to, direct transfection or vectors that facilitate access of the siRNA to the interior of the cell. Thus, examples of these vectors are, but are not limited to, retroviruses, lentiviruses, adenoviruses, adeno-associated viruses, Herpes simplex viruses, non-viral DNA plasmids, cationic liposomes, and molecular conjugates. Thus, for example, the siRNAs of the present invention, as well as RNA or DNA precursors of these siRNAs, can be conjugated with delivery peptides or other compounds to promote the transport of these siRNAs into the cell.

The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, that is, molecules that contain an antigen-binding site that specifically binds (immunoreacts with) the protein. NK-R1. Examples of portions of immunologically active immunoglobulin molecules include F (ab) and F (ab ') 2 fragments that can be generated by treating the antibody with an enzyme such as pepsin. It can be a monoclonal or polyclonal antibody.

Antibodies capable of binding to the NK-R1 protein can be used to inhibit the activity of said protein. Such antibodies are commercially available and / or are easily obtainable by the person skilled in the art by known methods. Antibodies, or fragments thereof, might be capable of inhibiting the activity of the NK-R1 protein that contributes to viral infection, and the development of SARS. Antibodies can be polyclonal (typically include different antibodies directed against different determinants or epitopes) or monoclonal (directed against a single determinant on the antigen). The monoclonal antibody can be biochemically altered, by genetic manipulation, or it can be synthetic, the antibody possibly lacking in whole or in parts, portions that are not necessary for the recognition of NK-R1 and being replaced by others that they impart additional advantageous properties to the antibody. The antibody can also be recombinant, chimeric, humanized, synthetic, or a combination of any of the above.

An "recombinant antibody or polypeptide" (rAC) is one that has been produced in a host cell that has been transformed or transfected with the nucleic acid encoding the polypeptide, or produces the polypeptide as a result of homologous recombination.

These rAc's can be expressed and targeted to specific cellular subcompartments when the appropriate sequences for intracellular trafficking are incorporated into them. These antibodies are called intrabodies, and they have been shown to be effective not only in diverting proteins from their usual compartment or blocking interactions between proteins involved in signaling pathways, but also in activating intracellular proteins.

Also part of the invention are genetic DNA constructs capable of transcribing to a peptide, antibody or antibody fragment, for use as an antiviral against coronavirus infection, and in the treatment of SARS. Said genetic DNA construction would direct the in vitro or intracellular transcription of the antibody sequence or fragment thereof, and comprises at least one of the following types of sequences: a) DNA nucleotide sequence, preferably double-stranded, which comprises, at least, the coding sequence of the antibody of the invention or of the antibody fragment of the invention for its in vitro or intracellular transcription, b) DNA nucleotide sequence, preferably double-stranded, corresponding to a system or vector of gene expression comprising the coding sequence of the antibody sequence or antibody fragment of the invention operatively linked with at least one promoter that directs the transcription of said nucleotide sequence of interest, and with other sequences necessary or appropriate for transcription and its adequate regulation in time and place, for example, start and stop signals, cleavage sites, polyadenylation signal, origin of replication, transcriptional activators ( enhancers ), transcriptional silencers ( silencers), etc. .. for use in pathological contexts that occur with infection.

A "ribozyme" as understood in the present invention refers to a catalytic polynucleotide (typically RNA), which can be constructed to specifically recognize, by hybridization, an mRNA and fragment or eliminate its expression. Ribozymes can be introduced into the cell as catalytic RNA molecules or as genetic constructs that are expressed as catalytic RNA molecules.

One skilled in the art could prepare organic molecules that can specifically bind to NK-1R without binding to other polypeptides or proteins. The organic molecules will preferably have a weight of 100 to 20,000 daltons, more preferably 500 to 15,000 daltons, and more preferably 1000 to 10,000 daltons. Libraries of organic molecules are commercially available. The route of administration can be, but is not limited to, intraperitoneal, intrathecal, intravenous, intramuscular, subcutaneous, intraventricular, oral, enteral, parenteral, intranasal, or dermal.

NK-1R antagonists include, but are not limited to, aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orvepitant maleate, casepitant, ezlopitant, serlopitant, befetupitant, and maropitant

Therefore, in another preferred embodiment of this aspect of the invention, the neurokine-1 receptor (NK-1R) modulating agent is an antagonist of NK-R1 receptors, and more preferably it is selected from the list consisting of: aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orvepitant maleate, casepitant, ezlopitant, serlopitant, befetupitant and maropitant, or any of their pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.

In another even more preferred embodiment, the neurokine-1 receptor (NK-1R) modulating agent is aprepitant, or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.

Apripetant is a drug of formula (I):

IUPAC name 3 - [[(2R, 3S) -2 - [(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy] -3- (4-fluorophenyl) morpholin-4-yl] methyl] -1,4-dihydro-1,2,4-triazol-5-one

And CAS number 170729-80-3

PHARMACEUTICAL COMPOSITION AND PHARMACEUTICAL FORM OF THE INVENTION

A second aspect of the invention refers to a pharmaceutical composition, hereinafter the pharmaceutical composition of the invention, which comprises at least one modulating agent of the neurokine-1 receptor (NK-1R) or any of its salts, esters, tautomers , solvates and pharmaceutically acceptable hydrates, or any of their combinations, for use as an antiviral for the prevention, improvement, relief and / or treatment of coronavirus infection, It also refers to the pharmaceutical composition of the invention for the prevention, improvement , relief and / or treatment of severe acute respiratory syndrome (SARS) caused by the coronavirus. Preferably the coronavirus is SARS-CoV-2 (COVID-19)

Additionally, the pharmaceutical composition of the invention further comprises a pharmaceutically acceptable carrier , an excipient or a pharmaceutically acceptable vehicle.

In another preferred embodiment, the pharmaceutical composition of the invention comprises as the only active principle the modulating agent of the neurokin receptor-1 (NK-1R). Most preferably he is a neurokine-1 receptor antagonist. More preferably the neurokine-1 receptor modulating agent is an antagonist, and even more preferably it is selected from the list consisting of: aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orvepitant maleate, casepitant, ezlopitant, serlopitant, befetupitant and maropitant, or any of their pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.

In another even more preferred embodiment, the neurokine-1 receptor (NK-1R) modulating agent is the NK-R1 aprepitant antagonist, or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any of its combinations.

The pharmaceutically acceptable adjuvants and vehicles that can be used in said compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the preparation of therapeutic compositions.

In the sense used in this description, the expression "therapeutically effective amount" refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, it will be determined, among other causes, due to the characteristics of the compounds, including the age, the patient's condition, the severity of the alteration or disorder, and the route and frequency of administration.

The compounds described in the present invention, their salts, prodrugs and / or solvates as well as the pharmaceutical compositions containing them can be used together with other drugs, or active principles, additional to provide a combination therapy. Said additional drugs can form part of the same pharmaceutical composition or, alternatively, they can be provided in the form of a separate composition for their simultaneous administration or not to that of the pharmaceutical composition comprising a modulating agent of the neurokine-1 receptor (NK- 1R) of the invention, preferably an NK-1R receptor antagonist, or a salt, prodrug or solvate thereof. Even more preferably an NK-1R receptor antagonist is selected from the list consisting of: aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orvepitant maleate, casepitant, ezlopitant, serlopitant, befetupitant and maropitant, or any of their salts, esters, pharmaceutically acceptable tautomers, solvates and hydrates, or any combination thereof, and still much more preferably aprepitant, or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof. Therefore, in another embodiment. Preferably, the pharmaceutical composition further comprises another active ingredient. More preferably, the active ingredient is selected from the list consisting of: antivirals (such as, but not limited to, Favilavir, Remdesivir, Galidesivir, Lopinavir, Ritonavir, Rivabirin, Darunavir, Cobicistad, or any of their combinations), chloroquine, hydroxychloroquine, IL-6 antagonists, such as Tocilizumab, or Remdesivir, or any of its combinations.

It also refers to a combined preparation, hereinafter combined preparation of the invention, comprising:

a) A composition of the invention,

b) A composition comprising another active ingredient, for its combined administration separately, simultaneously or sequentially for the prevention, amelioration, alleviation or treatment of coronavirus viral infection, and / or for the prevention, amelioration, relief or treatment of SARS .

It should be emphasized that the term "combined preparation" or also called "juxtaposition", in this specification, means that the components of the combined preparation do not need to be present as a bond, for example in a true composition, in order to be available for their combined application. , separate or sequential. In this way, the expression "juxtaposed" implies that it is not necessarily a true combination, in view of the physical separation of the components.

As used herein, the term "active substance", "active substance", "pharmaceutically active substance", "active ingredient" or "pharmaceutically active ingredient" means any component that potentially provides a pharmacological activity or other different effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals. The term includes those components that promote a chemical change in the manufacture of the drug and are present therein in a modified form intended to provide the specific activity or effect.

Another aspect of the invention relates to a pharmaceutical form, hereinafter the pharmaceutical form of the invention, comprising the compound of the invention or the composition of the invention.

In this specification, "pharmaceutical form" is understood as the mixture of one or more active principles with or without additives that have physical characteristics for their adequate dosage, conservation, administration and bioavailability.

In another preferred embodiment of the present invention, the compositions and pharmaceutical forms of the invention are suitable for oral administration, in solid or liquid form. The possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, such as aggregating agents (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (eg lactose, sugar, cornstarch, calcium phosphate, sorbitol or glycine), disintegrants (eg starch, polyvinyl pyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate. Other pharmaceutical forms can be colloidal systems, including nanoemulsions, nanocapsules and polymeric nanoparticles.

Compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as a mixture and dispersion. The tablets can be coated following methods known in the pharmaceutical industry.

The compositions and pharmaceutical forms can be adapted for parenteral administration, as sterile solutions, suspensions, or lyophilisates of the products of the invention, using the appropriate dose. Suitable excipients, such as pH buffering agents or surfactants, can be used.

The above-mentioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries and in other reference texts.

The term "drug", as used herein, refers to any substance used for the prevention, diagnosis, alleviation, treatment or cure of diseases in man and animals.

The administration of the compounds, compositions or pharmaceutical forms of the present invention can be carried out by any suitable method, such as intravenous infusion and the oral, topical or parenteral routes. Oral administration is preferred for the convenience of patients.

The administered amount of a compound of the present invention will depend on the relative efficacy of the chosen compound, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1,2, 3 or 4 times daily, with a total dose between 0.1 and 1000 mg / Kg / day. It is important to note that it may be It is necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.

The compounds and compositions of the present invention can be used together with other drugs in combination therapies. The other drugs can be part of the same composition or a different composition, to be administered at the same time or at different times.

Throughout the description and claims the word "comprise" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge in part from the description and in part from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.

EXAMPLES OF THE INVENTION

EXAMPLE 1.

MATERIAL AND METHODS

We study the presence of SP peptides homologous dipeptide domains in COVID-19 virus proteins. The spike surface glycoprotein of the COVID-19 virus has 1273 aa (Figure 1)

(https://www.ncbi.nlm.nih.gov/protein/QHU79204.1

). The nucleocapsid phosphoprotein of the COVID-19 virus has 419 aa (Figure 2) (https://www.ncbi.nlm.nih.gov/protein/QHW06056.1

). The membrane glycoprotein of the COVID-19 virus has 222 aa (Figure 2) (https://www.ncbi.nlm.nih.gov/protein/QHW06062.1

). The envelope protein of the COVID-19 2019-nCoV virus has 75 aa (Figure 2) https://www.ncbi.nlm.nih.gov/protein/QHU79206.1

RESULTS

After checking the proteins of the COVID-19 virus. We show that the COVID-19 spike surface glycoprotein virus has 1273 aa containing 24 homologous SP: 15 dipeptides of C-terminal sequence (Figure 1): Gln-Phe (134 135; 926-927), Phe -Phe (58-59), Phe-Gly (96-97; 337-338; 565-566; 592-593; 797 798; 878-879; 969-970), Gly-Leu (545-546; 857- 858; 1223-1224), Leu-Met (176-177; 1049-1050) and 7-amino terminal sequence KP (462-463; 811-812) PQ (207-208; 579-580; 1112-113) QQ (563-564; 1010-1011) (Figure 1). The 419 aa COVID-19 virus nucleocapsid phosphoprotein contains 15 homologous dipeptide domains SP: 5 of the C-terminal sequence Gln-Phe (306-307), Phe-Gly (17-18; 274 275; 286-287) , Gly-Leu (44-45) and 10 N-terminal sequence RP (41-42) PK (142-143; 168-169; 257-258), KP (257-258), PQ (162-163; 302 -303; 383-384), QQ (239-240; 241-242) and 1 SP C-terminal homologous tripeptide Phe-Phe-Gly (314-316) (Figure 2). The 222 aa COVID-19 viral membrane glycoprotein contains 2 N-terminal homologous SP dipeptide domains (131-132), PK (165-166) and 1 SP Gly-Leu-Met homologous tripeptide domain (89-91 ) (Figure 2) and the 75 aa COVID-19 virus envelope protein contains 1 dipeptide N domain of the SP dipeptide domain (53.53) (Figure 2).

It is described for the first time that COVID-19 virus proteins increase surface glycoprotein, nucleocapsid phosphoprotein, membrane glycoprotein and envelope protein contain homologous tripeptide and tripeptide domains of SP respectively (Figure 1 and 2 ). This is consistent with the presence of SP homologous dipeptides and tripeptides in HIV, RSV, MV and EMCV viral entry / binding proteins is a common feature and this suggests that viruses mimic SP sequences included in viral entry / binding proteins. upon entry, through the NK-1R, into the host cell (Muñoz et al. 2019). Therefore, COVID-19 virus proteins could bind to the homologous peptide domain of SP NK-1R through SP to enter host cells. Interestingly, the spike surface glycoprotein expresses the homologous dipeptide domain SP Gln-Phe (134-135), Phe-Phe (58-59), Phe-Gly (96-97), Leu-Met (176- 177) (Figure 1) similar to SP C-terminal Gln-Phe-Phe-Gly-Leu-Met (Figure 1). This means that the COVID-19 spike surface glycoprotein expresses it. amino acid sequence of the C-terminal sequence of SP that is essential for affinity and the minimal fragment of SP that retains good affinity for the NK-1R. Here we show that the COVID-19 spike virus protein has homologous dipeptides and tripeptides SP (Figure 1) similar to SP (Figure 1).

In addition, the surface glycoprotein of the COVID-19 spike virus contains SP homologous dipeptides and tripeptides (Figure 1) for possible binding to NK-1R cells. Due to the surface of the spike, the glycoprotein binds with NK-1R. The use of NK-1R antagonists (aprepitant and rolapitant) inhibit the COVID-19 virus.

Virus replication

Furthermore, SP after binding to NK-1R cells is known to be a mitogen in normal and tumor cells. NK-1R is expressed in normal and tumor cells. Interestingly, VZV infection of human spinal astrocytes induced nuclear localization of full-length and truncated NK-1R in the absence of the endogenous ligand, SP. Thus, SP after binding to NK-1R could induce nuclear localization of NK-1R for mitogenesis and, similarly, integument protein VZV expressed by SP-like functions induces nuclear translocation of NK-1R, promoting lamellipodia formation and viral spread in spinal astrocytes). In the case of SARS-CoV-2 or COVID19, if NK-1R receptor antagonists are administered, it would block the replication and multiplication of the virus.

Neurogenic inflammation

The hallmarks of neurogenic inflammation are vasodilation, increased vascular permeability, plasma extravasation, edema formation, and leukocyte infiltration. Endothelial cells are known to express NK-1R and SP is a key mediator in neurogenic inflammation. Furthermore, macrophages and monocytes express NK-1R and that SP stimulates macrophages and human peripheral blood monocytes by regulating NFkB to produce inflammatory cytokines, which include IL-1, IL-6, IL_8, IL-12 and TNF. The antagonists NK-1R L-733,060 and CP-96345 would block inflammation and the release of inflammatory cytokines. Furthermore, selective inhibition of NK-1R with the NK-1R antagonist CP-122721 has been shown to eliminate neurogenic inflammation in RSV-infected intrapulmonary airways.

The COVID-19 virus mimics SP by the SP homologous peptide domain similar to the C-terminal of SP and can induce this exaggerated neurogenic inflammation through the overexpression of NK-1R from lung cells. The present inventors show that the use of the NK-1R antagonist such as, but not limited to, aprepitant and the drug rolapitant, can abolish neurogenic inflammation and cytokine release in COVID-19 lung infection.

The envelope protein ( E) is necessary for pathogenesis.

The NK-1R antagonists, aprepitant and rolapitan, are used in nausea and vomiting. In humans, aprepitant (300 mg / day for 6 weeks) exerted the same antidepressant effect as paroxetine and was very well tolerated, and the reported side effects for aprepitant were similar to those of placebos. In HIV patients, aprepitant (375 mg / day for 2 weeks) decreased the number of CD4 PD-1 positive cells, soluble CD163 cells, and the plasma level of SP and was safe and well tolerated. It has recently been reported in combination therapy (aprepitant and radiotherapy) to treat a patient with lung cancer. The patient was treated for 45 days with radiotherapy and aprepitant (1,140 mg / day) and, after six months of treatment, the lung tumor mass disappeared. The patient improved his clinical condition and no side effects were observed. This means that the aprepitat drug is safe, and has a wide therapeutic window.

SP homologous peptide domain: COVID-19 surface glycoprotein has 1273 aa containing 24 SP homologous dipeptides, 419 aa nucleocapsid phosphoprotein contains 18 SP homologous dipeptide domains and 1 SP homologous tripeptide. The 222 aa membrane glycoprotein contains 3 SP homologous dipeptide domains and 1 SP homologous tripeptide domain and the 75 aa envelope protein contains 1 SP homologous dipeptide domain. We suggest the same way for SP binding to NK-1R. NK-1R ligation of COVID-19 SP-like protein region sequences could be crucial for COVID-19 for virus pathogenesis (virus entry into cells, virus replication and viral shedding) and clinical severity.

As shown in the invention, the use of NK-1R antagonists, such as, but not limited to, aprepitant and rolapitant, is useful in the treatment of COVID-19 infection because it counteracts the functions of viral proteins of NK-1R-mediated SP-type COVID-19. Also, the use of aprepitant is safe. Therefore, NK-1R antagonists, such as, but not limited to, aprepitant and rolapitant, are useful as antiviral drugs in the treatment of COVID-19 virus infection.

In summary, the use of receptor antagonists NK-1R is useful for the prevention, improvement, relief and / or treatment of coronavirus viral infection, acting at the different levels that we have just discussed, and therefore, for prevention , improvement, relief and / or treatment of SARS.

EXAMPLE 2. CLINICAL TRIAL

MAIN GOAL.

To determine the efficacy of aprepitant, an NK-1 receptor antagonist, as a treatment for SARS-Covid-19 compared to conventional therapy.

TYPE and DESIGN.

Open study, pilot type. Phase II clinical trial of the use of aprepitant (NK-1 receptor antagonist) in the treatment of patients with Covid-19.

PATHOLOGY UNDER STUDY.

Patients infected by Covid-19 and with severe acute respiratory syndrome (SARS-CoV-2)

MAIN VALUATION VARIABLE.

Evaluation of the anti-inflammatory response, especially at the pulmonary level through laboratory tests and other diagnostic imaging tests, necessary to assess the evolution of the process or disease.

TYPE OF POPULATION.

Hospitalized male and female patients over 18 years of age, with a diagnosis confirmed by PCR in oropharyngeal samples and / or Covid-19 serology and with criteria for severe cases defined according to protocols with laboratory data (ferritin, leukocytes, (DD)), clinical and radiological that will be susceptible to the need for mechanical ventilation.

Sample size :

27 patients randomly divided into 3 groups or cohorts of 9 patients:

1) 9 patients with standard treatment.

2) 9 patients with standard treatment and aprepitant 750 mg / day orally.

3) 9 patients with standard treatment and aprepitant 1,140 mg / day orally.

Treatment scheme:

Patients receive a single daily dose, according to the assigned group or cohorts, of aprepitant (EMEND®), orally, for an initial period of 14 days. In case of partial response to treatment, those in group 2 are rescued in group 3, the administration of the drug will be continued for a new period of 14 days, in all cases as long as there is no evidence of a serious undesirable effect attributable to the treatment.

Description of treatment:

Generic name: Aprepitant

ATC code: A04A D12

Trade name: Emend®

Pharmaceutical form: hard gelatin capsules.

Composition: Aprepitant (80 or 125 mg), sucrose, microcrystalline cellulose (E460), hydroxypropyl cellulose (E463).

Concomitant treatments

For all patient groups, all concomitant treatments will be collected. The following drugs can be used although with caution because they can increase the levels of aprepitant

- CYP3A4 inducers: rifampicin, phenytoin, carbamazepine, phenobarbital can reduce the plasma concentrations of aprepitant.

- CYP3A4 inhibitors (ketoconazole, itraconazole, Azithromycin, telithromycin, nefazodone, and protease inhibitors)

Evaluations of the anti-inflammatory response: DAYS 0, 48h, 96h and 7 days after starting treatment.

Claims (10)

1.- A modulating agent of the neurokinase-1 receptor (NK-1R) for the prevention, improvement, relief and / or treatment of coronavirus infection. 2. The modulating agent of the neurokinase-1 (NK-1R) receptor according to the preceding claim, where the coronavirus is SARS-CoV-2 or COVID19. 3. The modulating agent of the neurokinase-1 receptor (NK-1R) according to any of claims 1-2, for the prevention, improvement, relief and / or treatment of severe acute respiratory syndrome (SARS) caused by the coronavirus. 4. The modulating agent for use according to any of claims 1-3, wherein the modulating agent is a neurokinase-1 (NK-1R) receptor antagonist. 5. The modulating agent for use according to any of claims 1-4, wherein the agent is selected from a list consisting of: a) an organic molecule, b) an RNA molecule, c) an antisense oligonucleotide, d) an antibody, or e) a ribozyme. 6.- The modulating agent for use according to any of claims 1-5, wherein the modulating agent is an organic molecule that is selected from: aprepitant, rolapitant, netupitant, lanepitant, vestipitant, orvepitant maleate, casepitant, ezlopitant, serlopitant , befetupitant and maropitant, or any of their pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any of their combinations. 7. The modulating agent for use according to the preceding claim, wherein the agent is aprepitant, of formula (I), or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any of their combinations.

8. A pharmaceutical composition comprising at least one modulating agent for use according to any of claims 1-7. 9. The pharmaceutical composition for use according to claim 8, further comprising a pharmaceutically acceptable carrier , an excipient or a pharmaceutically acceptable vehicle. 10. The pharmaceutical composition for use according to any of claims 8-9, further comprising another active ingredient.