ANTIVIRAL DRUGS RESISTANCY = RESISTANCE VIRUS

1. ANTIVIRAL DRUGS RESISTANCY = RESISTANCE VIRUS HOW ?

3. LEVEL OF THINKING STRATEGY FOR ANTIVIRAL DRUGS DEVELOPMENT Non-Specific GENERAL VIRUSES  INFLUENZA VIRUSES  INFL UENZA VIRUS-A  AVIAN INFLUENZA  H5N1  ..THE NEXT MUTANT… WHAT MEDICINE WE ARE LOOKING FOR ? RESISTANCE Specific

4. VIRUS LIFE CYCLE  VIRAL DRUGS TARGET RESISTANCY (VIETNAM) 1 2 3 RESISTANCY (VIETNAM & THAILAND) 4

5. Difference in: Receptor / Target Drugs Structure Potency Difference in: Adsorption Penetration Uncoating

6. ANTI-VIRAL IMMUNORESPONSES SEVERE ACUTE RESPIRATORY SYNDROME IMMUNOPATHOLOGY

7. 1 PREVENTIVE THER ANTI-VIRAL ANTIBODY DRUG 2 IMMUNOTHERAPY 3 IMMUNOTHERAPY 4

9. available antiviral drugs • THE PROBLEMS : • RESISTANCY • IMPORT

10. TamifluR Oseltamivir is an ethyl ester prodrug which requires ester hydrolysis to be converted to the active form, oseltamivir carboxylate [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate. The discovery of oseltamivir was possible through rational drug design utilising available x-ray crystal structures of sialic acid analogues bound to the active site of the influenza virus neuraminidase (Lew 2000). Oseltamivir was developed through modifications to the sialic acid analogue framework (including the addition of a lipophilic side chain) that allow the drug to be used orally (Kim 1998). The structural formula is as follows:

11. The chemical name of zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-en onic acid RelenzaR Zanamivir is an orally inhaled powder currently approved in 19 countries for the treatment of, and in two for the prophylaxis of influenza A and B. Zanamivir is a competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective cycle of influenza viruses. It closely mimics sialic acid, the natural substrate of the neuraminidase

12. Chemically, rimantadine hydrochloride is alpha-methyltricyclo-[3.3.1.1/3.7]decane-1-methanamine hydrochloride, with a molecular weight of 215.77 FlumadineR Rimantadine is an M2 ion channel inhibitor which specifically inhibits the replication of influenza A viruses by interfering with the uncoating process of the virus. M2 inhibitors block the ion channel formed by the M2 protein that spans the viral membrane (Hay 1985, Sugrue 1991). The influenza virus enters its host cell by receptor-mediated endocytosis. Thereafter, acidification of the endocytotic vesicles is required for the dissociation of the M1 protein from the ribonucleoprotein complexes. Only then are the ribonucleoprotein particles imported into the nucleus via the nuclear pores. The hydrogen ions needed for acidification pass through the M2 channel. Rimantadine blocks the channel (Bui 1996).

13. Against this exciting background comes the news of drug resistance. Virally encoded drug resistance has been documented against nearly all compounds with antiviral activity, and the genetic basis of resistance is now known. • Summary points • Resistance has developed to nearly all specific and effective antiviral agents • Resistance has developed to all drugs against HIV, and treating hepatitis B with nucleoside analogue monotherapy gives rise to drug resistant variants • Resistance develops rapidly when viral replication is not maximally suppressed • Drug resistant viruses may be transmitted • Assays to measure drug resistance are available in specialised laboratories

15. REVERS TRANSCRIPTASE (RNA  DNA )  RNA

16. REVERSE TRANSCRIPTASE azidothymidine Non-nucleoside reverse-transcriptase inhibitors (NNRTIs)

17. REVERSE TRANSCRIPTASE RESISTANCY

18. REVERSE TRANSCRIPTASE RESISTANCE

19. RESISTANCE

21. RESISTANCE

22. PROTEASE Panel A shows the amino acid chains of both subunits of the protease. The protease inhibitor (ritonavir) occupies the central substrate-binding domain of the enzyme. The sites of amino acid residues most frequently involved in resistance to protease inhibitors are shown as red beads. The designation of the corresponding residues is written in red for the first subunit of the protease and in blue for the other subunit.

23. RESISTANCE In Panel B, the substrate-binding cavity contains a protease inhibitor (lopinavir) in the context of either the sensitive protease (green) or the resistant protease (red).

25. PROTEASE RESISTANCE

26. MUTASI  RESISTEN RESISTANCE

28. VIRUS MUTATION  CHANGE IN DRUGS TARGET : • Reverse transcriptase • Protease • Virus surface protein SOAL UAS : Apa …… Bagaimana …… STOP

29. Viral resistance to enfuvirtide usually results from mutations located in a stretch of 10 amino acids within HR1. Interestingly, changes in amino acids in gp41 outside HR1 — and even changes in gp120 — appear to be associated with significant differences in the susceptibility of the virus to enfuvirtide. These mutations or polymorphisms probably explain the remarkably wide range of natural susceptibility to enfuvirtide among HIV-1 strains and could participate in the evolution of acquired resistance to enfuvirtide.

34. TamifluR : Oseltamivir ? STRUCTURE ACTIVITY RELATIONSHIP BASED DRUG SHORTCUT-DISCOVERY : ? SYNTHESIS  FROM MEDICINAL PLANTS ? RelenzaR : Zanamivir FlumadineR : Rimantadine