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Drugs targeting DNA and RNA

Targeting DNA or RNA . i) Alter regulation of replication, transcription or translation ii) Kill cells, not alter regulationGeneral problems i) Poor tissue specificity, leading to side effects and high toxicity ii) Mutagenic, teratogenic and carcinogenic properties. Important aspects of D

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Drugs targeting DNA and RNA

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    1. Drugs targeting DNA and RNA Objectives: A number of drugs target DNA and RNA.  At the end of the lecture, the student will be aware of the classes of low-molecular weight drugs that target DNA and RNA, including specific examples.  In addition, knowledge of the forces important for the binding strength and specificity of those drugs will be presented. Small molecules vs. oligonucleotides as drugs

    2. Targeting DNA or RNA i) Alter regulation of replication, transcription or translation ii) Kill cells, not alter regulation General problems i) Poor tissue specificity, leading to side effects and high toxicity ii) Mutagenic, teratogenic and carcinogenic properties

    3. Important aspects of DNA and RNA structure

    4. Watson-Crick base pairs

    5. DNA conformational flexibility Structure of the GCTATAAAAGGCA 13-mer from the TATA-box binding protein crystal structure

    6. DNA intercalators

    7. DNA minor groove binders

    8. Structure of  Distamycin A bound to DNA

    9. Combine intercalation with minor groove binding

    10. Alkylating Agents i) Wide variety of alkylations of DNA/RNA possible N7 of Gua or Ade (also N2 and N3 atoms) Both SN1 and SN2 mechanisms ii) Many alkylating agents are mutagenic and/or carcinogenic iii) Also react with other biomolecules iv) Generally block synthesis of DNA v) Both monofunctional and bifunctional alkylating agents are known. Some bifunctional agents can crosslink DNA strands.

    11. SN1 and SN2 mechanisms

    12. Metabolic activation of Benzo(a)pyrene leading the alkylation of DNA

    13. Nitrogen Mustards

    14. Platinum containing agents

    15. Nucleotide analogs incorporated into DNA

    16. RNA directed agents

    17. Ribosome http://www.molgen.mpg.de/~ag_ribo/ag_franceschi/ Protein/RNA complex that synthesizes proteins (translation) Some antibiotics target the ribosome erythromycins tetracyclines aminoglycosides

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