antiviral drugs （抗病毒药） 2011.12

Antiviral drugs （抗病毒药）

2011.12

Shanghai Jiao Tong University

HIV

Shanghai Jiao Tong University Virus StructureVirus Structure

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

Shanghai Jiao Tong UniversityVirus-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 ……

Shanghai Jiao Tong Universityviral 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。

Shanghai Jiao Tong UniversityHIV life cycle

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HIVµ°°×Ã¸ºóÆÚÐÞÊÎ ±»PIsÒÖÖÆ

Ï¸ °ûÄ¤

×°Åä

²¡ ¶¾µ°°×

Ë«Á´DNA

Ï¸ °ûÄÚ

· Òë

²¡ ¶¾mRNA

±àÂëRNA

²¡ ¶¾RNA

×ªÂ¼

ÕûºÏ

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被

抑制

RTIs

Fusion through viral gp41 and loss of its envelope, th

e uncoating

Viral DNA formation by reverse transcriptase follow

ed by RNase

Viral DNA entry to the host cell nucleus through

its nuclear pores

Splicing of viral RNA by host RNA

polymerase to produce viral mRNA

Migration of viral RNA to the cytoplasm as mRNA to encode the synthesis

of viral proteins

Breakdown of the polyprotein precursor by the protease to give structural proteins and enzymes

Binding of the virus to the T-cell through the gp120

and CD4 receptors

Shanghai Jiao Tong Universityanti-viral attack steps


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


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


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


DNA polymerase inhibitors


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

Used for herpes （疱疹病毒）infections

Shanghai Jiao Tong UniversityMechanism of aciclovir

aciclovir

↓viral thymidine kinase

acyclo-guanosine monophosphate (acyclo-GMP)

↓cell kinase

acyclo-GTP

↓ viral DNA polymerase

incorporated into viral DNA

↓ chain termination


Reverse transcriptase inhibitors

逆转录酶抑制剂


ViralRNA

double helix DNA

Incorporated into host genome

reverse transcriptase HIV integras

e

transcriptiontranslation

Polyproteins

Final structural proteins

HIV protease

Drugs

reverse transcriptase inhibitors

Protease inhibitor


Zidovudine （齐多夫定）Thymidine （胸苷） analog, competitive inhibitor of reverse transcriptase

First approved drug used for the treatment of HIV/AIDS

Shanghai Jiao Tong UniversityLamivudine （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


Lamivudine （拉米夫定）

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


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

Shanghai Jiao Tong University reverse transcriptase inhibitor

Nevirapine （奈韦拉平）

1996, FDA approved 1st non-nucleotide reverse transcriptase

Nevirapine binds allosterically at a distinct site away from the active site termed the Non-nucleotide reverse transcriptase pocket

Used for HIV infection


Nevirapine (奈韦拉平， red) is shown inside a pocket of reverse transcriptase, a viral enzyme that is essential to

HIV.

Receptor specificity

Successful example of CADD


Protease inhibitors

蛋白酶抑制剂


Disadvantages of reverse transcriptase inhibitors:

Unable to eradicate AIDS

Severe side effects

HIV resistance


ViralRNA

double helix DNA

Incorporated into host genome

reverse transcriptase HIV integras

e

transcriptiontranslation

Polyproteins

Final structural proteins

HIV protease

Drugs

reverse transcriptase inhibitors

Protease inhibitor

P55, …


Nelfinavir （奈非那韦）

HIV-1 and HIV-2 protease inhibitors

Side effects

Resistance

Recombination therapy needed

Saquinavir

Ritonavir

indinavir

Shanghai Jiao Tong University“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”

Shanghai Jiao Tong University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


《 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。

Shanghai Jiao Tong UniversityDisadvantages of cocktail

Only effective at early stage of AIDS

More adverse effects

Expensive, but getting cheaper


Neuraminidase inhibitors

神经氨酸酶抑制剂


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

Shanghai Jiao Tong Universityanti-viral attack steps


Broad spectrum antiviral drugs

广谱抗病毒药


Ribavirin （利巴韦林）

Mechanisms complex, remains elucidated

Used to treat viral respiratory infection; hepatitis C; viral hemorrhagic fevers; …

Shanghai Jiao Tong UniversityInterferons （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）


阅读材料： Ashfaq UA, Yousaf MZ, Aslam M, Ejaz R, Jah

an S, Ullah O. siRNAs: potential therapeutic agents against hepatitis C virus. Virol J. 2011; 8:276

antiviral drugs （抗病毒药） 2011.12

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