1. Antiviral Drugs: An Overview Prof. Sri Agus Sudjarwo.,Ph.D

2. The Outline 1.Viruses, what are they, who are they? 2.Virus Classifications 3.The virus, its hidden personal life 4.Methods of Attack 5.Drug Development 6.Antiviral Drugs 7.Conclusions and Overview

3. Different living organisms

4. Many different shapes Stages of replication May attack: Animals Plants Bacteria (Phages)

5. The Virus’ Personal Life

8. Stages of replication - DNA virus Attachment, penetration, uncoating, transfer of DNA to cell nucleus Assembly Release: Budding thru membranes (knoppskyting) Lysis Oncogenic viruses

9. Stages of replication - RNA virus More difficult to treath RNA virus infect. More mutation - Less repair mech. than with DNA (+) stranded RNA = mRNA Alternative A: (-) RNA virus Alternative B: (+) RNA virus (≠Retrovirus)Alternative C: Retrovirus; (+) RNA virus

10. Antiviral Drugs Amantadine and analogs Neuraminidase Inhibitors Nucleoside analogs - Antimetabolites Other comp. that interfere with replication Comp. that interfere with translation (protein synth) Interferon / interferon inducers Specific retroviral drugs Reverse transcriptase inhibitors Nucleosides (NRTIs) Non-nucleosides (NNRTIs) Protease inhibitors Effect against influenza A viruses No longer in use N. Inhib. penetration of RNA virus Inhib. uncoting

12. Neuraminidase Inhibitors Effect on influenza virus A and B(?) Inhib. neuraminidase (enzyme that breaks bonds between HA* in newly HA in formed virus and host cell) Prevents release of virus HA: Hemaglutinin, (glycoprotein) important for bonding between influenza virus and host

13. ≈ S N 1 ≈ TS ‡ Zanamivir Relenza® Oseltamivir Tamiflu® (“Take my flu”)

14. Binding of oseltamivir to NA Basic centre better binding than DANA Hydrophobic pocket

15. Nucleoside analogs - Antimetabolites (C.f. anticancer compounds) Aciclovir® Zovirax® Valtrex® Guanosine analog Activity: DNA Herpes viruses (ex. Herpes simplex, varicella, cytomegalo, epstein barr)

16. Normal DNA / RNA chain

17. Relatet Structures Cymevene® Valcyte® Converted to triphosphates Inhibitors of viral DNA polymerases Gancyclovir: Not dependent of viral thymine kinase (better effect CMV, EB)

18. Ribavirin Copegus® Rebetol® Guanosine analog Fosforylated to triphosphate in vivo Inhib. viral RNA polymerase, RNA / DNA synthesis Broad spectrum (RNA and DNA viruses, some effect on HIV) Used against Hepatitis in N., serious side effects Thymidine analogs R = I, X = OH R = I, X = NH 2 (less tox) R = Br, X = OH R = F, X = OH R = CF 3, X = OH Incorp. DNA - faulty viral proteins Cytosine analogs Cytarabine (ARA-C) Cytarabin®, Cytosar®, Only cancer ther in N.

19. Adenosine analogs Fludarabine Fludara® cancer ther. Isolated Streptomyces antibioticus First studied as anticancer drug Interfere with DNA synth Tox. Rapid metab. adenosine deaminase Other comp. that interfere with replication Foscarnet Foscavir® Not orally avail. No in vivo activation required Inhib. DNA polymerase Neurotox. Also active against HIV Comp. that interfere with translation (protein synth) One of the oldest antiviral comp. known Inhib protein synth Methisazone

20. Interferon / interferon inducers Interferon: Rel small glycoproteins formed in virus infected cells (leukocytes, fibroblasts) Binds to surphase of other cells Initiates events leading to inhib. of mRNA trascrib. and translation Host spesific (not virus spesific) Interferon Inducers Double stranded RNA Heparin Dextranes Other bioplolymers Tilorone Side effects

21. Retrovirus HIV (humans) Animal viruses resulting in cancer / AIDS 15-39% http://www.who.int/hiv/facts/hiv2003/en/

22. Stages of replication - RNA virus Alternative C: Retrovirus; (+) RNA virus Specific retroviral drugs Reverse transcriptase inhibitors Nucleosides (NRTIs) Non-nucleosides (NNRTIs) Protease inhibitors

23. Nucleoside Reverse Transcriptase Inhibitors Nucleoside analogs without 3’ OH - DNA chain termination Pro-drugs - Phosphorylated by kinases in vivo Zidovudine (AZT) Retrovir® Trizivir® Kombi prep. Stavudine Zerit® Zalcitabine (ddC)Lamividine (3TC) Epivir® Trizivir® Compivir ® Kombi prep. Didanosine (ddI) Videx® Abacavir (ABC) Trizivir® Kombi prep.

24. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Efavirenz / Sustiva Stocrin® Nevirapin Viramune® J Med Chem 2004, 5923 FDA 1998 Already resistance activity resist strains Wild type RT mutated Binds directly to TR

25. Protease Inhibitors Solomon “oppgitt emne” Dec. 10th The HIV-1 protease is an enzyme crucial for the maturation and assembly of infectious viral particles

26. Science 1990, 249, 527 The two subunits are rotated 180 from each other J. Med. Chem. 1990,33, 2687 Design of C2 sym. comp. as TS(Intermed) analog of Phe-Pro cleavage (Type 1 comp. did not lead to drugs) X-ray: HIV-1 protease - C2 symmetric homodimeric -Not C2-sym. in related human proteases!

27. Ritonavir Norvir® -Bad water sol. and oral bioavail. -X-ray indicate modification of Cbz allowed M w >500! -Somewhat lower Mw -Thiazol instead of pyridine -FDA March 1996, now many resistant strains -Ritonavir inhib. 3A4 isozyme of CypP450 Used in combi. with other protease inhib. to suppress their metab.

28. Saquinavir (green) bound to HIV-1 Protease Saquinavir Fortovase® Indinavir Crixivan® Nelfinavir Viracept® Amprenavir Agenerase® Lopinavir Kaletra®