ANTIVIRAL DRUGS

Constraints in antiviral therapy:

• Because viruses are obligate intracellular parasites, identification of safe and

effective antiviral therapies is difficult.
• Antivirals must enter the host cells to act against viruses, because of the close
aqssociation between virus and host cell, these agents are likely to to be toxic to
the host cell also.
• They must disrupt the biochemical metabolism of the viral cells
• Most of the antiviral drugs are active on the replicating virus, not effective
against the latent virus: thus therapy has to be started in the incubation period
itself, i.e. has to be prophylactic
• A virus cannot replicate on its own, It must attach to and enter a host cell, It then
uses the host cell’s energy to synthesize protein, DNA, and RNA

• The best antiviral drugs inhibit a specific step in viral replication or pathogenesis.

• The emergence of virus mutants resistant to antiviral drugs is a serious problem.

• Combination of targeted delivery strategies to control toxicities and resistance.

Some barriers to effective antiviral drugs

- Selective toxicity for virus functions
- Therapeutic index
- Resistance due to rapid mutation of many viruses
- Intracellular – can’t use non-permeable drugs
- Symptoms usually occur at height of viral replication
- Latency or non-replicating phases hard to target
- Limited capability for rational drug development
STAGES OF VIRAL REPLICATION/ INFECTION IN A HOST CELL
1. Attachment – virus attach to the host cell receptors(nonspecific; may be
neurotransmitters or enzymes) on host cell membrane
2. Penetration – penetration of host cell by formation of endosome
3. Uncoating – nucleoprotein layer is separated and nucleic acid is free in cytosol
4. Transcription - synthesis of RNA( mRNA) by DNA dependent RNA
polymerase or transcriptase in DNA and RNA viruses respectively.
5. Translation –binding of viral mRNA to host ribosomes; structural proteins
(glycoproteins)and functional proteins(enzymes) are formed
6. Replication –synthesis of duplicate strands of genetic material and viral induced
enzymes by using original RNA or DNA
7. Assembly –Nucleic acid, functional and structural proteins are assembled
together forming the mature viral particles
8. Release – Mature viral particle gets released by budding or lysis and
infect the fresh cells.
 POSSIBLE PHASES OF LIFE CYCLE ON WHICH ANTI-VIRAL ATTACK
MIGHT BE LAUNCHED

The life cycle of a virus comprises several stages such as binding to the cell surface,
replication, protein synthesis etc. and all of these stages may be the target of anti-viral
drugs. Among the life cycle stages that have been targeted by potential therapeutic
agents are:
• Attachment of the virus to the cell surface, perhaps as a result of competition with
a specific viral receptor.
• Uptake into intracellular vesicles (endosomes)
• Uncoating of virus (loss of protein coat, fusion of lipid membrane with
endosome/lysosome). Note: the endosome/lysosome compartment is acidic and
inhibition of acidification of this compartment might be a good target.
• Integration of the viral DNA into chromosomal DNA of the host cell (where this
occurs).
• Transcription of genome to new RNA or DNA (polymerases are the target).
• mRNA transcription
• mRNA processing (poly adenylation, methylation, capping, splicing)
• Translation to protein
 • Post-translational modification of proteins (glycosylation, phosphorylation, fatty
acylation, proteolysis). Some of these are essential for functional, infective viral
progeny.
• Assembly of the components into the whole virus

Factors affecting the respone to therapy : Competent immune system:- Best response
to viral infections; A well-functioning immune system will eliminate or effectively
destroy virus replication.

Immunocompromised individuals have frequent viral infections like Cancer clients,

especially leukemia or lymphoma,Transplant clients, due to pharmacological
therapy,AIDS clients, the disease that attacks immune system

Viruses killed by current antiviral therapy includes- Cytomegalovirus (CMV), Hepatitis

viruses, Herpes viruses, Human immunodeficiency retro) virus (HIV), Influenza viruses
(the “flu”), Respiratory syncytial virus (RSV)

CLASSIFICATION OF ANTIVIRAL DRUGS

A. BASED ON THEIR TARGET / MECHANISM OF ACTION

I. AGENTS SPECIFIC TO VIRAL ENZYMES /VIRUSES

1.Protease inhibitors(protein processing inhibitors/ inhibitor of post translational

events)--saquinavir, indinavir , amprenavir, lopinavir, ritonavir, nelfinavir ,. atazanavir ,
bevirimat etc

2. Inhibitor of viral attachment (fusion) and penetration- pooled immunoglobulins,

hyper immune sera, enfuvirtide, etc

3. Inhibitors of Uncoating- amantadine, rimantadine, arildone , and the WIN

compounds ; pleconaril

4. Immunomodulators- interferons

5. DNA polymerase (DNA syntheis) inhibitors- aciclovir(acyclovir/ acycloguanosine),

foscarnet(PFA,phosphonoformicacid),ganciclovir,penciclovir,valganciclovir,cidofovir,ral
tegravir,ribavirin(tribavirin),neplanocin (vidarabine,) etc

6. Nucleoside Reverse transcriptase inhibitors- zidovudine (Azidothymidine,AZT),

stavudine,sorividine,zalcitabine(dideoxycytidine:DDC),didanosine(dideoxyinosine;DDI),
lamivudine, abacavir , emtricitabine , tenofovir etc

7 Non Nucleoside Reverse transcriptase inhibitors- nevirapine, elaviridine,

delavirdine , efavirenz
8.RNA synthesis(RNApolymerase)inhibitors-ribavirin(tribavirin),vidarabine(
neplanocin)

9.Protein synthesis inhibitors-Fomivirsen

10. Protein modification inhibitors

i) Glycosylation inhibitors-2-deoxyglucose D-glucosamine (2-dG)

ii) Sialidation/ Neuraminidase inhibitors-oseltamivir(Tamiflu),zanamivir(Relenza)

II. AGENTS AFFECTING VIRAL/ CELLULAR ENZYMES

Nucleoside analogs - Idoxuridine(Iodo-deoxyuridine) ,Trifluorothymidine (Trifluridine) ,

cytarabine, vidarabine, ribavirin (tribavirin)

B. BASED ON THE ACTIVITY AGAINST PARTICULAR VIRUS

a. Antiherpes drugs- acyclovir(acyclovir), foscarnet, valaciclovir, ganciclovir,

cidofovir , famciclovir ,penciclovir, idoxuridine

b. Antiretroviral (HIV)drugs- zidovudine (Azidothymidine,AZT), stavudine,

zalcitabine, didanosine( DDI), abacavir , emtricitabine , tenofovir , nevirapine,
elaviridine, efavirenz , saquinavir, indinavir , amprenavir, lopinavir, ritonavir, raltegravir
etc

c. Antiinfluenza drugs- amantadine, rimantadine(Influenza A only ), oseltamivir,

zanamivir etc

d. AntiHepatitisB,C,D –interferon alpha, lamivudine

e. Anti Respiratory syncytial virus- tribavirin(ribavirin) , palivizumab

f. Anti Cytomegalo virus-ganciclovir, foscarnet, oidofovir

g. Anti rhinovirus- WIN compound for picorna virus

1. INHIBITOR OF VIRAL ATTACHMENT (FUSION) AND PENETRATION

Enfuvirtide

• Peptides derived from glucoprotein 41 can inhibit infection, probably by blocking

the interaction of gp41 with cell membrane proteins during fusion or by stopping
the conformational change that results from the association of two gp41
molecules and which is necessary for fusion.
• Enfuvirtide is a 36 amino acid peptide that corresponds to residues 127-162 of
gp41 and blocks this conformational change.
• low bioavailability and the emergence of resistant mutants are the problem

Immunomodulators

• prepared from pooled plasma to contain predominantly IgG selected for high
titres of antibody (hyper immune) for specific viruses
• Most effective when used prophylactically than therapeutically
• Newborn calves- administration of colustrum to prevent neonatal scours, enteric
infections , immunoglobulins for hepatitis A, B and rabies in humans are the
examples.

II. INHIBITORS OF UNCOATING

Uncoating of the virus (i.e. the loss of the lipid envelope of membrane- containing viruses
or the loss of nucleocapsid proteins in non-enveloped viruses) often occurs in low pH
endosome or lysosomes, as the result of a pH-dependent fusogen

Pleconaril
• Binds picornavirus capsid proteins , Blocks conformational change needed for
uncoating (loss of VP4 and lipid required) .
• Potential for polio, colds (rhinovirus), viral meningitis, etc.
• Concern about interaction with oral contraceptives
• Can be used in life-threatening picornavirus disease

Amantadine and Rimantidine (Ion channel blocking agents)

• Effective against influenza A but not B. , also effective against paramyxo, togg,
myxoviruses(RNA viruses)
• The M2 protein, is a small protein associated with the membrane of the virus,
functions as an ion channel at two stages of viral replication within the host cell.
It acts as ion channel a) for proton influx from the endosome in to the interior of
the viroion befor e viral membrane and endosomsal membrane fusion occurs b)
at the later stage of assembly and release of the new virions at the host cell
surface.
 • Amantadine and Rimantidine bind to this M2 protein and and blocks its ion
channel activity preventing viral uncoating , resulting in inhibition of the viral
replication in early and at later stages

NUCLEIC ACID SYNTHESIS -The best anti-viral drugs that we have are of this type.
They are selective because: the virus may use its own enzyme to activate the drug
and/or the viral polymerases may be much more sensitive to the drug than the
corresponding host enzymes

Thymidine kinase substrates

• The thymidine kinase of herpes simplex (and other) viruses allows the virus to
grow in cells that do not have a high concentration of phosphorylated nucleic acid
precursors. These are usually cells that are not replicating their genome (e.g.
nerve cells). Resting cells do, however, have unphosphorylated nucleosides. By
bringing in its own kinase, the virus can grow in non-dividing cells by
phosphorylating the cells' nucleosides.
• The name of the enzyme is a bit of a misnomer since it can work on other
nucleosides than thymidine (thymidine happens to be the best substrate), i.e. the
enzyme is non-specific as to substrate. This is in contrast to the host cell
thymidine kinase which is very specific to thymidine since the cell has other
enzymes to phosphorylate the other nucleosides.
• This lack of specificity of the viral enzyme allows it also to work on nucleoside-
analog drugs and phosphorylate them. The host enzyme, because of its greater
specificity, is much less good at this (and often does not phosphorylate the drug at
all).
• The fact that the viral enzyme is quite good at phosphorylating the drug has
another advantage. As it can be administered in a non-phosphorylated form. This
is useful as it is difficult to get phosphorylated drug into the cell because plasma
membranes are poorly permeable to phosphorylated compounds in the absence of
a specific transport protein.
• The great use of these drugs results from the facts that

- they are only activated by the virus-infected cell

- the activated form of the drug is rendered even more specific as a result of the
viral DNA polymerase being more sensitive to the drug than the host enzyme.

III. DNA SYNTHESIS (DNA polymerase ) INHIBITORS

Acyclovir/Acycloguanosine.- Acyclovir is a nucleoside analog similar to guanosine, but

contains an acyclic sugar group, this is very selective and one of the better anti-viral
drugs.

• Higly selective and extremely safe

 • It is non-toxic to uninfected cells (except some renal dysfunction) because it is
not activated by uninfected cells (because the drug is a poor substrate for the very
specific cell thymidine kinase).
• Moreover, the DNA polymerase of herpes simplex virus is 10 times more
sensitive than cellular DNA polymerase.
• Activation of the drug requires thymidine kinase activities to be present in the
cell to convert acyclovir to a triphosphate derivative, the actual antiviral drug.
• Acyclovir triphosphate competes with GTP to incorporate in to DNA , leading to
chain termination
• It is effective against herpes simplex keratitis, latent HSV, fever blisters (H.
labialis), genital herpes. less so against varicella-zoster virus (VZV).
• Acyclovir-resistant mutants are a problem after long term use and have been
shown to result from changes in the thymidine kinase or polymerase gene.

Valaciclovir
• is a prodrug form of acyclovir called which is an L- valine ester of the drug.

Famciclovir
• This is a prodrug of Penciclovir and is converted to Penciclovir as a result of
oxidation and the hydrolysis of the two ester groups.
• Because of the esterification, it is soluble in water and can be administered orally.

Ganciclovir
• This drug is very similar to Acyclovir, it just has an extra -OH. It is also available
as a pro-drug called Valganciclovir which is an L-valine ester of Ganciclovir
• Oral will probably to replace intravenous Ganciclovir for therapy and prevention
of cytomegalovirus (CMV) infections. Ganciclovir is active against CMV for
which it is the drug of choice.
• As with Acyclovir, Ganciclovir targets the viral DNA polymerase and acts as a
chain terminator. In herpes virus-infected cells, it is phosphorylated first by the
viral thymidine kinase and then by cell kinases to yield the triphospho form of the
drug which is incorporated into and terminates the DNA chain. However, CMV
does not encode a thymidine kinase. Instead,
• Ganciclovir is phosphorylated by a CMV-encoded protein kinase (UL97) which
accounts for its specificity for infected cells.
• Selectivity is also achieved because the viral polymerase has 30 times greater
affinity for Ganciclovir than the host enzyme Adenosine arabinoside

Foscarnet sodium

• structural analog of inorganic phosphorous (pyrophosphate analog),

• This is a competitive inhibitor of DNA polymerase - it binds to pyrophosphate
site., because of structural resemblance and inhibits the binding of nucleotide
with the DNA polymerase resulting in DNA chain termination.
• It is useful when the infecting virus has gained resistance to other drugs such as
Acyclovir
IV. REVERSE TRANSCRIPTASE INHIBITORS

Zidovudine,(Azidothymidine,AZT) stavudine and sorividine

• are thymidine analogs, are converted by the cellular /host cell

enzymes(kinases/phosphorylases) to their respective triphosphate forms, which
act as false nucleotides resembling thymidine phosphate, and competitively
inhibiting the binding of deoxythymidine triphosphate, which otherwise is the
naturalsubstrate.
• Subsequently these triphosphates are incorporated in to the growing DNA chain
at the place of natural nucleotide by binding with reverse transcriptase and
inhibiting DNA elongation resulting in breakage/ termination or false elongation.

• It is phosphorylated by a cell kinase and so it can be used against viruses without

their own thymidine kinase
• Reverse transcriptase (RNA-dependent DNA polymerase) is more sensitive to
the drug than human DNA-dependent DNA polymerase accounting for the
specificity but there are severe toxicity effects.
• It is used as an anti-HIV type 1 and type 2 drug
• Because of the use of RNA polymerase II in the synthesis of the viral genome of
retroviruses and the consequent high rate of mutation of the virus, the selective
pressure of the presence of the drug rapidly leads to the emergence of resistant
viral mutants. All of these have mutations in reverse transcriptase.
• Because of the emergence of resistant mutants, AZT is administered in
combination with other drugs

Cidofovir
• Cidofovir is both a DNA chain terminator and DNA polymerase inhibitor. It
is an acyclic nucleoside phosphonate (not a phosphate) in which the C-O-P
bond in a nucleoside monophosphate has been replaced by a phosphonate (C-
P) bond that provides an enzymatically stable derivative with a long half life.
• The drug is administered in the phosphonomethoxy-nucleoside form and is
phosphorylated twice intracellularly to the active diphosphate form using
two cellular kinases (pyrimidine nucleoside monophosphate kinase and
pyrimidine nucleoside diphosphate kinase.
• A viral kinase is not involved, in contrast to acyclovir which is administered
as the nucleoside form and the first phosphate is added by viral thymidine
kinase).
• It inhibits the DNA polymerases of a number of viruses at concentrations
that are substantially lower than those needed to inhibit human DNA
polymerases.
• It is active against herpes viruses with fewer side effects than Ganciclovir
although it does show nephrocytotoxicity and a number of other side effects
• It must be administered along with probenecid in order to block renal tubular
secretion of the drug.
 • Cidofovir is particularly useful in the treatment of cytomegalovirus and is
indicated for the treatment of CMV retinitis in patients with AIDS.
• It may be useful for treatment of acyclovir-resistant herpes infections. It is
also active against pox viruses, including the molluscum contagiosum virus,
polyoma virus, and adenoviruses

Dideoxyinosine(Didanosine: ddI)
• is adenosine analog, converted by by cellular enzymes in to didanosine
triphosphate, which competitively inhibits the binding of deoxy adenine
triphosphate(natural substrate) with reverse transcriptase.
• This is used in AZT-resistant patients and in combination drug treatments along
with AZT

Zalcitabine( Dideoxycytosine,ddC) and Lamivudine

• cytosine analogs, convertd in to their respective triphosphates , which
competitively inhibit the binding of deoxycytosine triphosphste to the reverse
transcriptase resulting in breakage/termination.
• As with AZT, there is pronounced toxicity because of lack of specificity to the
viral polymerase and the rapid emergence of resistant mutant strains.

Tenofovir

• Tenofovir is active against retroviral and hepatitis B reverse transcriptase and is a

chain terminator.
• It is often used in combination with lamivudine and a non-nucleoside reverse
transcriptase inhibitor, efavirrenz.
• It should not be used in combination with lamivudine and abacavir(

Idoxuridine (IDU)

• Thymidine analog that are incorporated into DNA by the viral DNA
polymerase.
• They form unstable base pairs and mis-translation results in mutant proteins.
• They are competitive inhibitors of the viral DNA polymerase after intracellular
phosphorylation. in to triphosphate, which interfere with the binding of
deoxythymidine phosphsate with DNA polymerase, resultimg in incorporation
of false nucleotide.
• used mainly in eye drops or a topical cream for herpes simplex keratitis. Pox
viral infections

Trifluorothymidine (Trifluridine)

• similar in its mode of action to IDU.

• It also is activated by viral thymidine kinase.
 • TFT is used as a topical cream or in eye drops for herpes simplex keratitis.

V. IMMUNOMODULATORS:

INTERFERONS IFN is induced by accumulation of double stranded RNA (dsRNA).

• IFN induces gene expression at the transcriptional level after binding to specific cell
surface receptors.
• A cell that is bound to interferon and responds to it is in an antiviral state.
• Ifn induces expression of more that 100 genes, products of many of these genes possess
broad spectrum antiviral activity.
• They lead to cell death by apoptosis or programmed cells death, limiting cell to cell
spread of virus.
• Production of large amounts if IFN causes common symptoms such as fever, chills,
nausea, etc.
• It is in use for hepatitis B and C; side effects problematic

IFN-gamma is induced only when certain lymphocytes are stimulated to replicate and
divide after binding a foreign antigen.
IFN -alpha and beta are induced by viral infection of any cell type

VI. NON-NUCLEOSIDE INHIBITORS OF REVERSE TRANSCRIPTASE

Non-nucleoside inhibitors are the most potent and selective reverse transcriptase
inhibitors, which have high therapeutic index and also show good bioavailablity so that
anti-viral concentrations are readily achievable. They are non-competitive reverse
transcriptase inhibitors that target an allosteric pocket on the reverse transcriptase
molecule . These drugs might be useful in combination therapy since there is a limit to
the number of mutations that reverse transcriptase can bear without losing function.

Nevirapine

In monotherapy, this drug causes an initial fall in the number of HIV virions but
resistance sets in and virus titers rise again to a high level. This drug has been
approved for therapy in AIDS patients.

Delavirdine

This is a bis (heteroaryl) piperazine compound.. The drug is absorbed rapidly. It

is used in combination with a nucleoside analog such as AZT and the protease
inhibitors
Efavirenz
Efavirenz used in combination with other drugs, can suppress viral load at least
as well as the protease inhibitor Indinavir in the equivalent combination with
nucleoside reverse transcriptase inhibitors.

VII. RNA SYNTHESIS INHIBITORS

Ribavirin

• This drug is not a pyrimidine or a purine., It may act as a guanosine analog

• It inhibits influenza RNA polymerase non-competitively in vitro but poorly
in vivo.
• It is phosphorylated by cellular kinase in to ribavirin mono phosphate,
which then inhibits inosine monophosphate dehydrogenase, an enzyme
essential for the synthesis of GTP. GTP is an essential component for DNA
synthesis and its inhibition results in the decrease of the cellular pool of GTP
, preventing DNA synthesis
• It also inhibits capping process of 5' end of mRNA. The cap normally
contains methyl guanosine. The inhibition blocks proterin synthesis
• However, ribavirin is known to inhibit the production of infectious polio
virus and this virus does not have a methyl guanosine cap; so there must be
alternative mechanisms for ribavirin action.
• Also directly inhibits RNA dependent RNA polymerase of influenza virus
• It is likely that this drug introduces multiple mutations into viral RNA
rendering it incapable of a new round of cell infection

Vidarabine

• a potent inhibitor of S-adenosylhomocysteine hydrolase, may also inhibit capping

of mRNA.
• S-adenosylhomocysteine hydrolase inhibitors have been shown to exert anti-viral
activity against pox-, paramyxo-, rhabdo-, filo-, bunya-, arena-, and reoviruses.
• They also interfere with the replication of HIV by inhibition of the Tat
transactivation process

VIII. PROTEIN SYNTHESIS INHIBITORS

Little progress has been made in the development of drugs that inhibit viral protein
synthesis since viruses use host cell translation mechanisms. Only one drug in this class
is available.

Fomivirsen

• It is an anti-sense oligonucleotide made of 21 nucleosides that are

phosphorothioate stabilized
• It can be administered as an intra-ocular injection for Cytomegaloviral retinitis.
It specifically hybridizes to the mRNA for CMV immediate early 2 protein,
blocking its translation

IX. PROTEIN PROCESSING INHIBITORS - PROTEASE INHIBITORS

(INHIBITORS OF POST TRANSLATIONAL EVENTS)
Many viruses must cleave the proteins that they make. In the case of surface
glycoproteins, this is usually carried out by a host protease in the secretory pathway (e.g.
in Golgi body). In the case of internal proteins, such as the polymerase or the group-
specific antigens (GAGs) of retroviruses and some other viruses, there is a viral protease
that is encoded in the gene

Protease inhibitors inhibit the proteases, the enzymes responsible for cleaving the
major poly proteins to yield various structural and functional proteins, essential for the
replication cycle. Thus inhibition of the protease can block the cleavage of the viral
poly protein, preventing virus replication. They are most commonly used in combination
with reverse transcriptase inhibitors

Saquinavir

• is a hydroxyethylamine transition-state analog of the cleavage site on a protein

recognized by the HIV protease.
• It is the least bio-available of the present protease inhibitors and is the least
effective.
• All are Cyp 450 enzyme inhibitors, thus drug interactions possible.

Ritonavir.

• It is used as part of a triple drug highly active anti-retroviral therapy (HAART)

Others-Indinavir, Amprenavir,Nelfinavir Lopinavir. Atazanavir,

Bevirimatare are general inhibitors of the HIV aspartyl protease.

X. PROTEIN MODIFICATION INHIBITORS

i) Glycosylation inhibitors

2-deoxyglucose and D-glucosamine

• is a glucose analog interfering with the synthesis of oligosaccharidews of

viral surface glycoproteins. (glycosylation process- a last step in viral
replication)
• Inhibits wide range of enveloped DNA and RNA viruses – orthomyxo,
paramyxo and herpes.
• Potential application in the prophylaxis of canine distemper, equine influenza
and parainfluenza infections.

Castanospermine (a natural product derived from a species of Australian chestnut .

 ii) Sialidation (NEURAMINIDASE INHIBITORS)
Two glycoproteins are found on the surface of influenza viruses; the
hemagglutinin and the neuraminidase (sialidase).

Neuraminidase has several functions. It allows the virus to move through mucous
secretions in the respiratory tract so that it may infect new cells. Since sialic acid is the
influenza receptor, it is necessary to remove sialic acid from the surface of the infected
cell and of the virus so that viral particles may escape.The neuraminidase is therefore
very important for the spread of the virus from cell to cell. .

Neuraminidase inhibitors
• Less CNS side effects, but more Gastro-Intestinal effects
• More expensive, but there is less risk of inducing virus resistance. block the
active site of neuraminidase; prevents removal of sialic acid residues and results
in clumping of viral progeny. Inhibits virus release from surface
• Effective against influenza A & :B
• Resistance less frequentl than with the ion channel blockers amantadine or
rimantadine

Zanamivir

• a potent inhibitor of the viral neuraminidase of types A and B influenza viruses

• . This is important as the previously available drugs such as rimantadine are
ineffective against influenza type B.
• The design of Zanamivir is based on the three-dimensional structure of the
neuraminidase..

Oseltamivir

• is a carbocyclic sialic acid analogue that can be given orally.

• Popular prophylactic antiinfluenza drug used in case of “bird flu” outbreak.

RNA CLEAVAGE ENZYMES

Ribozymes are RNA molecules that have catalytic properties among which are the
specific cleavage of nucleic acids. Heptazyme is a ribozyme that cleaves hepatitis C RNA
at highly conserved regions (thereby reducing the possibility of the development of
resistance). It recognizes and cuts all known types of the hepatitis C virus, thereby
stopping viral replication. Heptazyme has not been successful in clinical trials.

OTHER TARGETS

In the retrovirus life cycle, the targeting of the specific protease that is necessary for the
formation of an infectious virus particle has been particularly successful. Earlier, reverse
transcriptase inhibitors had also been successful but the nucleoside analogs cause severe
side effects because they also inhibit the host's DNA polymerase. In contrast, the non-
nucleoside inhibitors of reverse transcriptase show excellent therapeutic indices. In each
case, however, monotherapy leads to the rapid emergence of resistant mutants. Many
other possible targets for intervention in the life cycles of viruses are under investigation
and, of course, the goal is specificity. In the case of the retroviruses, in addition to those
drugs described above, inhibitors of the integrase are being extensively studied but none
has yet made it to the clinic as routine treatment