Chapter 21 Antiviral Agents 抗病毒药物

1. Chapter 21 Antiviral Agents 抗病毒药物 20-400 nm

2. The A(H1N1) Virus 甲型H1N1病毒 2009，April Influenza A virus subtype H1N1, also known as A(H1N1), is a subtype of influenzavirus A and the most common cause of influenza (flu) in humans. Some strains of H1N1 are endemic in humans, including the strain(s) responsible for the 1918 flu pandemic which killed 50–100 million people worldwide. H1N1 strains caused roughly half of all flu infections in 2006.

3. Virus Structure and Classification Viruses consist of a nucleic acid core that contains either DNA or RNA The protein coat called an envelope, which is composed of glycoproteins, important virus antigens The glycoprotein become attached to the receptor Sites (polypeptide) on the host cell HIV virus picture The penetration, uncoating, and release of the virions（病毒体） in the host cell depend on the structural coat proteins

4. Viral Replication and Transformation 病毒的复制和转化 • Attachment • Penetration • Uncoating and transfer of viral DNA to nucleus • Early transcription into viral mRNA • Early translation of viral mRNA into enzymes for viral DNA synthesis • Synthesis of viral DNA and late • transcription of viral mRNA • Late translation of mRNA into viral structural proteins • Assembly of virus particles in nucleus • Budding from nucleus and release of virions

5. Viral Drug Therapy Agents inhibiting virus attachment, penetration and early viral replication 抑制病毒复制早期的药物 Amantadine 金刚烷胺 Tricyclic primary amine 三环伯胺 Mechanism of Action: Amantadine inhibits penetration of RNA virus particles into the host cell; the early stages of viral replication 金刚烷胺抑制RNA病毒穿透宿主细胞 Clinical Application: Amantadine is effective clinically in preventing and treating all A strains of influenza, particularly A2 strains of Asian influenza virus

6. Amantadine （金刚烷胺） • Pharmacokinetics（药代动力学）: • Half-life is 15-20 hour • 90% is excreted unchanged by the kidney • There are no reports of metabolic products • Side Effects（副作用）: • Generally, the drug has low toxicity at therapeutic level • Severe central nervous system (CNS) symptoms（中枢神经系统）

7. Rimantadine （金刚乙胺） • Mechanism of Action: • More effective than amantadine hydrochloride against influenza A virus • Interfere with virus uncoating by inhibiting release of specific proteins • It may act by inhibiting RT or the synthesis of virus-specific proteins • Pharmacokinetics: • The half-life of rimantadine in adults ranges from 24-36 hours • Over 90% of rimantadine doses were absorbed in 3-6 hours

8. Interferon （干扰素） • Interferon are polypeptide hormones, or glycoproteins, MW 20-160kD • It is produced by the cells immune system in response to foreign challenge, like virus, parasites or tumor cell Types of Interferon: according to the type of receptor through which they signal Type α,β,γ Interferon Induction: “inducers” Various small molecules and large polymers Tilorone， 替洛隆

9. Neuraminidase Inhibitors （NA，神经氨酸酶抑制剂） NA is found in both influenza A and B viruses NA is a glycoprotein The viruses are bound to the NA through the sialic acid （唾液酸） and the NA cleaves the sialic acid moiety Sialic acid hydrolysis catalyzed by neuraminidase 神经氨酸酶催化的唾液酸水解

10. Structural derivatives of sialic acid as neuraminidase inhibitors 唾液酸衍生物作为神经氨酸酶抑制剂 6-C ring, prodrug

11. Agents Interfering with Viral Nucleic Acid Replication • 干扰病毒核酸复制的药物 Mechanism of Action: Binding to DNA or RNA polymerase, competitive binding Vs native substrate 1) Nucleoside：Pyrimidine 核苷类：嘧啶 脱氧胸腺嘧啶苷 碘苷 • Idoxuridine is a nucleoside containing a halogenated pyrimidine and is an analogue of thymidine • Acts against DNA viruses

12. Idoxuridine Mechanism of Action: 链终止 • Idoxuridine is first phosphorylated by the host cell to an active triphosphate form • The phosphorylated drug is incorporated during viral nucleic acid synthesis by a false pairing system that replaces thymidine, results in chain termination. Active form

13. Other Nucleoside Pyrimidine Analogue Inhibitors 阿糖胞苷 氟苷 溴苷 三氟胸苷 Pyrimidine analog Same mechanism Anticancer Same mechanism Increased potency

14. 2 Purine Analogs （嘌呤核苷类） Vidarabine 阿糖腺苷 Streptomyces antibioticus 链霉菌 Mechanism of Action：Cellular enzymes convert Vidarabine to mono, di-, and triphosphate derivatives that interfere with viral nucleic acid replication Metabolism of Vidarabine 阿糖腺苷的代谢 Adenine deaminase 腺嘌呤脱氨酶

15. Acyclovir（阿昔洛韦）and Valaciclovir （伐昔洛韦） Acyclovir is a synthetic analogue of deoxyguanosine（脱氧鸟苷）, The carbohydrate moiety is acyclic The active form is the triphosphate form

16. Mechanism of Action • Acyclovir is converted to monophosphate, di- and tri-phosphate form This phosphorylation reaction occurs faster by cells infected by virus than by normal cells • Viral DNA polymerase （DNA 聚合酶）is competitively inhibited by triphosphate form at lower concentrations than is cellular DNA polymerase The triphosphate is incorporated into the viral DNA chain during DNA synthesis Lacks of the 3’OH of a cyclic sugar, terminates further elongation of the DNA chain • Preferential uptake of acyclovir by virus –infected cell results in a higher • concentration of acyclovir triphosphate, which leads to a high ratio of • therapeutic value to toxicity ratio of infected cells to normal cells

17. Mechanism of Action 胸苷激酶 鸟嘌呤核苷单磷酸激酶

18. Synthesis of Acyclovir 鸟嘌呤

19. Drawback of Acyclovir oxidation 地昔洛韦 阿昔洛韦 18 times enhanced solubility Good absorption Decreased side effect Prodrug, be oxidized to acyclovir in vivo Poor water solubility Poor absorption Drug resistance

20. More Acyclovir Related Drugs 伐昔洛韦 更昔洛韦 Higher potency Toxicity，活性高，毒性大 Good GI absortption 肠胃吸收好 泛昔洛韦 喷昔洛韦 Stable triphosphate form Longer half-life 三磷酸酯稳定，半衰期长 Better bioavailability 生物利用度较好

21. Non-nucleoside antiviral drugs • 非核苷类抗病毒药物 Ribavirin 利巴韦林 A guanosine analogue (X-ray crystallography) Broad-spectrum antiviral activity against both DNA and RNA viruses Mechanism of Action: It is phosphorylated to the triphosphate， resulting in inhibition of viral specific RNA polymerase, messenger RNA, and nucleic acid synthesis

22. Synthesis of Ribavirin triazole glycoside

23. Anti-HIV Agents 抗艾滋病药物 HIV virus Virus life cycle

24. Anti-HIV targets 1 Reverstranscriptase（逆转录酶）RNA-dependent DNA polymerase, is a DNA Polymerase enzyme that transcribes single-stranded RNA into double-stranded DNA 3D picture of reverstranscriptase Reverse transcriptase was discovered by Howard Temin at the University of Wisconsin-Madison, and independently by David Baltimore in 1970 at MIT. The two shared the 1975 Nobel Prize in Physiology or Medicine with Renato Dulbecco for their discovery.

25. 2 Protease 蛋白酶 HIV-1 protease (HIV PR) is an aspartic protease, HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion.

26. 3 Intergrase 整合酶 Integrase is an enzyme produced by a retrovirus (逆转录病毒，including HIV) that enables its genetic material to be integrated into the DNA of the infected cell. It is also produced by viruses containing double stranded DNAs for the same purpose. It is a key component in the pre-integration complex

27. Reverse Transcriptase Inhibitor: nucleoside, non-nucleoside 逆转录酶（RT）抑制剂：核苷类与非核苷类 Nucleoside Reverse Transcriptase Inhibitor: AZT 3’-azido-3’-deoxythymidine Zidovudine 齐夫多定 Mechanism of Action: the N3 group at 3’position, instead of OH, inhibits the 3’,5’diphosphate ester bond formation, chain terminator

28. Synthesis of AZT Deoxythymidine， 脱氧胸腺嘧啶核苷 Mechanism of Action: AZT is activated in vivo by thymidine kinase, Thymidylate kinase and nucleoside diphosphate kinase to AZTTP

29. Other NT Inhibitors 扎西他滨 司他夫定 去羟肌苷 拉米夫定 Pyrimidine analog High bioavailability Side effects: stomatitis, rash, fever, malaise, arthritis, et al Pyrimidine analogue High bioavailability Low toxicity Side effect: Pain, tingling, numbness in hands and feet Rapidly absorbed Through GI tract Combination with DDI, ddC or d4T Purine dideoxynucleoside Given in advanced HIV infection Side effect: Painful peripheral neuropathy and pancreatitis

30. Abacavir, ABC 阿巴卡韦 University of Minnesota College of pharmacy Dr. Robert Vince Dr. Mei Hua

31. Nonnucleoside RT Inhibitors (NNRTI) • 非核苷类 From structure-based drug design methodology Effective against AZT-resistant HIV strains Combination with ZDV and ddI Side effect: liver dysfunction and skin rashes Nevirapine 奈韦拉平 Mechanism of Action: Dipyridodiazepinone derivative , Binds directly to RT, blocks RNA- and DNA-dependent polymerase activity by causing a disruption of the enzyme’s catalytic site

32. HIV Protease Inhibitors • 蛋白水解酶抑制剂 HIV protease exists as a dimer Each monomer contains one aspartic residues at the active site Drugs are designed as transition-state mimetics to align at the active site • Peptide • Peptide mimetics • nonpeptide

33. Protease Inhibitors Ritonavir, 利托那韦 沙奎那韦 Indinavir, 茚地那韦 Nelfinavir, 萘非那韦 nonpeptide

34. Integrase inhibitors MK-0518, Merck, approved in Sept. 2007 2nd, GS-9139, approved in 2008, Gilead

35. The HAART （鸡尾酒疗法）： highly active antiretroviral therapy David Ho （何大一） Taiwanese American Time magazine, Man of the Year, 1996 Synergistic effect 1 + 1 > 2

36. Summary: DNA, RNA virus Virus replication cycle • Inhibit the earlier stage: • amantadine HCl, rimantadine HCl; • Interferon, α,β,γ; Inducer: tilorone • The Neuraminidase, NA inhibitor, transition state inhibitor • Agents interfere the nucleoside replication • Nucleoside, analogs of purine and pyrimidine • Nonnucleoside: structure-based drug design Mechanism of Action: activated in vivo by kinase to triphosphate form

37. Typical StructuresＩ

38. Anti HIV Agents, NNRT inhibitors

39. Protease Inhibitors Ritonavir, 利托那韦 沙奎那韦 Indinavir, 茚地那韦 Nelfinavir, 萘非那韦 nonpeptide

40. Integrase inhibitors MK-0518, Merck, approved in Sept. 2007 Generic name: Raltegravir 2nd, GS-9139, approved in 2008, Gilead