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Antiviral drugs (抗病毒药) 2011.12. HIV. Virus Structure. Virus contains a few proteins, lipids and nucleic acid which are accurately replicated by the infected cell to produce more viruses. Virus-induced diseases. Hepatitis (type A, B, C, …) Influenza AIDS Herpes (疱疹) - PowerPoint PPT Presentation
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Antiviral drugs (抗病毒药)
2011.12
Shanghai Jiao Tong University
HIV
Shanghai Jiao Tong University
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
½áºÏϸ °ûÍâ
HIVµ°°×øºóÆÚÐÞÊÎ ±»PIsÒÖÖÆ
ϸ °ûĤ
×°Åä
²¡ ¶¾µ°°×
Ë«Á´DNA
ϸ °ûÄÚ
· Òë
²¡ ¶¾mRNA
±àÂëRNA
²¡ ¶¾RNA
ת¼
ÕûºÏ
ÍÑ¿Ç
ϸ °ûºË
Äæת¼±àÂëRNA
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
Shanghai Jiao Tong University
Viral entry and uncoating inhibitors穿入和脱壳抑制剂
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
DNA polymerase inhibitors
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
Reverse transcriptase inhibitors
逆转录酶抑制剂
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
Protease inhibitors
蛋白酶抑制剂
Shanghai Jiao Tong University
Disadvantages of reverse transcriptase inhibitors:
Unable to eradicate AIDS
Severe side effects
HIV resistance
Shanghai Jiao Tong University
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, …
Shanghai Jiao Tong University
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
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
Shanghai Jiao Tong University
《 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
Shanghai Jiao Tong University
Neuraminidase inhibitors
神经氨酸酶抑制剂
Shanghai Jiao Tong University
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
Shanghai Jiao Tong University
Broad spectrum antiviral drugs
广谱抗病毒药
Shanghai Jiao Tong University
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)
Shanghai Jiao Tong University
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