Antiviral drugs （抗病毒药） 2011.12

1. Antiviral drugs（抗病毒药）2011.12

2. HIV

4. Virus Structure • Virus contains a few proteins, lipids and nucleic acid which are accurately replicated by the infected cell to produce more viruses.

5. Virus-induced diseases • Hepatitis (type A, B, C, …) • Influenza • AIDS • Herpes（疱疹） • 小儿巨细胞病毒(CMV)感染、先天性风疹致畸致残的重要病因 • 轮状病毒(RotV)引起腹泻病, 重者致患儿死亡 • 腮腺炎病毒致病毒性睾丸炎（15％－25％），不育 • ……

6. viral replication病毒的复制 ①病毒识别并吸附到宿主细胞的表面； ②通过宿主细胞膜穿入易感细胞； ③脱壳； ④合成早期的调控蛋白及核酸多聚酶； ⑤病毒基因组（DNA或RNA）复制； ⑥合成后期的结构蛋白； ⑦子代病毒的组装； ⑧易感细胞释放子代病毒。

7. HIV life cycle Binding of the virus to the T-cell through the gp120 and CD4 receptors Breakdown of the polyprotein precursor by the protease to give structural proteins and enzymes Fusion through viral gp41 and loss of its envelope, the uncoating Migration of viral RNA to the cytoplasm as mRNA to encode the synthesis of viral proteins Viral DNA formation by reverse transcriptase followed by RNase Splicing of viral RNA by host RNA polymerase to produce viral mRNA Viral DNA entry to the host cell nucleus through its nuclear pores

8. anti-viral attack steps

9. Viral entry and uncoating inhibitors穿入和脱壳抑制剂

10. Amantadine （金刚烷胺） • interfering with a viral protein——M2 (an ion channel), making virus "uncoating" impossible. • Prophylactic use in influenza virus A infection and Parkinson’s disease

11. Enfuvirtide（恩夫韦地） • Enfuvirtide binds to gp41, preventing the creation of an entry pore for the capsid of the virus, keeping it out of the cell. (entry or fusion inhibitor) • used in combination therapy for the treatment of HIV-1 infection

12. DNA polymerase inhibitors

13. Used for herpes（疱疹病毒）infections Aciclovir（阿昔洛韦） Ganciclovir（更昔洛韦）：≈aciclovir , 100 fold effective on cytomegaoviyns Valaciclovir（伐昔洛韦）：prodrug of aciclovir Famciclovir（泛昔洛韦）： ≈ aciclovir

14. Mechanism of aciclovir aciclovir ↓viral thymidine kinase acyclo-guanosine monophosphate (acyclo-GMP) ↓cell kinase acyclo-GTP ↓ viral DNA polymerase incorporated into viral DNA ↓ chain termination

15. Reverse transcriptase inhibitors 逆转录酶抑制剂

16. reverse transcriptase HIV integrase Incorporated intohost genome double helix DNA ViralRNA transcription translation Final structural proteins HIV protease Polyproteins reverse transcriptase inhibitors Drugs Protease inhibitor

17. Zidovudine（齐多夫定） • Thymidine（胸苷） analog, competitive inhibitor of reverse transcriptase • First approved drug used for the treatment of HIV/AIDS

18. Lamivudine（拉米夫定） • 1989, McGill University, Bernard Belleau, et al. designed as an antiviral agent • Yale University, Yung-Chi (Tommy) Cheng （郑永奇） cell culture effective against HBV • Lamivudine + zidovudine effective against HIV, accidentally found when a patient took zidovudine secretly while in a clinical trial of lamivudine monotherapy • Marketed by GSK

19. reverse transcriptase inhibitor • Used for treatment of chronic hepatitis B and HIV • Long term use leads to emergence of a resistant hepatitis B virus (YMDD) mutant Lamivudine（拉米夫定）

20. Adefovir dipivoxil（阿德福韦酯） • used for treatment of hepatitis B and herpes simplex virus（单纯疱疹病毒） infection • Ineffective against HIV

21. reverse transcriptase inhibitor • 1996, FDA approved 1stnon-nucleotide reverse transcriptase • Nevirapine binds allosterically at a distinct site away from the active site termed the Non-nucleotide reversetranscriptase pocket • Used for HIV infection Nevirapine（奈韦拉平）

22. Receptor specificity Successful example of CADD Nevirapine (奈韦拉平，red) is shown inside a pocket of reverse transcriptase, a viral enzyme that is essential to HIV.

23. Protease inhibitors 蛋白酶抑制剂

24. Disadvantages of reverse transcriptase inhibitors: • Unable to eradicate AIDS • Severe side effects • HIV resistance

25. reverse transcriptase HIV integrase Incorporated intohost genome double helix DNA ViralRNA transcription translation Final structural proteins HIV protease Polyproteins P55, … reverse transcriptase inhibitors Drugs Protease inhibitor

26. HIV-1 and HIV-2 protease inhibitors • Side effects • Resistance • Recombination therapy needed • Saquinavir • Ritonavir • indinavir Nelfinavir（奈非那韦）

27. “Cocktail” therapy • HIV不能精确地复制遗传信息，结构和功能的变化，致药物易失效 • HIV复制：亿～千亿新个体 / 天 • 一种药物时，HIV病毒仅小的变化就可以存活，甚或产生抗药性 • 3～4种药物（Cocktail)，作用于HIV感染的各个环节 • 70%～80%的病人体内病毒随着治疗下降，世界为之欢欣鼓舞 • 1996，美籍华裔科学家何大一被美国《时代》周刊评选为该年度风云人物 • 2001.1, 克林顿向他颁发了“总统国民勋章”

29. 何大一博士 祖藉江西，生于台中，长于美国 洛克菲勒大学艾伦·戴蒙德艾滋病研究中心主任、教授

30. 《Lancet》: “鸡尾酒疗法”1996年引入治疗以来，HIV病毒携带者和艾滋病患者的预期寿命已经平均延长了13.8年。

31. Disadvantages of cocktail • Only effective at early stage of AIDS • More adverse effects • Expensive, but getting cheaper

32. Neuraminidase inhibitors 神经氨酸酶抑制剂

33. Competitive neuraminidase inhibitor towards sialic acid, preventing new viral particles from being released by infected cells • used to treat and prevent influenza A virus and influenza B virus infection. Oseltamivir（奥司他韦） （商品名：达菲） H5N1 subtype

34. anti-viral attack steps

35. Broad spectrum antiviral drugs 广谱抗病毒药

36. Mechanisms complex, remains elucidated Used to treat viral respiratory infection; hepatitis C; viral hemorrhagic fevers; … Ribavirin（利巴韦林）

37. Interferons（干扰素） • Interferon α-2a：hairy cell leukemia, AIDS-related Kaposi’s sarcoma, and chronic myelogenous leukemia • Interferon α-2b （干扰素α-2b ）: chronic hepatitis B, C • Interferon β-1b and β-1a: multiple sclerosis • Interferon α-n3: genital and perianal warts（疣） caused by human papillomavirus（乳头状瘤病毒） • Interferon γ-1B：chronic granulomatous（肉芽肿） disease, and severe, malignant osteopetrosis（骨骼石化症）

38. 阅读材料： Ashfaq UA, Yousaf MZ, Aslam M, Ejaz R, Jahan S, Ullah O. siRNAs: potential therapeutic agents against hepatitis C virus. Virol J. 2011; 8:276