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1、Antiviral Agents,GAO Fen-Fei,Overview,Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell. Antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell.,Research in Antiviral Chemothe
2、rapy,In the early 1950s, IdUR and Trifluorothymidine(三氟胸腺嘧啶核苷) In the mid 1970s, Adenine arabinoside (Vidarabine,ara-A,阿糖腺苷) In the late 1970s, Acyclovir (阿昔洛韦) With the appearance of AIDS epidemic in the 1990s, Inhibitor reverse transcriptase or the protease,Antiretroviral (Anti-HIV) Agents,The fir
3、st available agents: Nucleoside analog class competitive inhibition of the viral reverse transcriptase Nonnucleoside reverse transcriptase inhibitors The protease inhibitors The combination of at least two antiretroviral agents (cocktail therapy) enhancing potency and delaying resistance,病毒RNA,互补双螺旋
4、DNA,掺入宿主基因组,反转录酶,HIV整合酶,转录翻译,多聚蛋白,小分子功能蛋白,HIV蛋白酶,Drugs,NRTIs,NNRTIs,PIs,ViralRNA,double helix DNA,Incorporated into host genome,reverse transcriptase,HIV integrase,transcription translation,Polyproteins,Final structural proteins,HIV protease,Drugs,NRTIs,NNRTIs,PIs,Nucleoside Reverse Transcriptase In
5、hibitors,Derivatives of Pyramine: AZT, ddC, d4T, 3TC Derivatives of Purine: ddI, ABC,Mechanism of Action,Competitive inhibition of HIV-1 reverse transcriptase; Incorporated into the growing viral DNA chain cause termination Drugs requires intracytoplasmic activation- phosphorylation triphosphate for
6、m Most have activity against HIV-2 as well as HIV-1.,Zidovudine,Azidothymidine (叠氮胸腺嘧啶), AZT Deoxythymidine analog anti-HIV-1 and HIV-2 Well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid. Eliminated primarily by renal excretion following glu
7、curonidation in the liver.,Decrease the rate of clinical disease progression and prolong survival. Treatment HIV-associated dementia(痴呆) and thrombocytopenia(血小板减少). Reduce the rate of vertical (mother-to-newborn) transmission of HIV. Adverse effect: myelosuppression(骨髓抑制) anemia or neutropenia; gas
8、trointestinal intolerance, headachs, insomnia(失眠),Zalcitabine (ddC),Cytosine analog Anti-HIV-1 Zalcitabine + Zidovudine + one protease inhibitor Long intracellular half-life of 10hs. Dose-dependent peripheral neuropathy. Contraindication to use with other drugs that may cause neuropathy.,Stavudine,T
9、hymidne analog (d4T), not used with AZT because AZT may reduce the phosphorylation of d4T. Anti-HIV-1 and HIV-2 High oral bioavailability (86%) that is not food-dependent. Plasma protein binding is negligible, mean cerebrospinal fluid concentrations are 55% of those of plasma. Excretion is by active
10、 tubular secretion and glomerular filtration.,Adverse effects: Dose-limiting toxicity is a dose-related peripheral sensory neuropathy. Pancreatitis, arthralgias(关节痛), elevation in serum aminotransferases(转氨酶).,Didanosine (ddI),Synthetic analog of deoxyadenosine Plasma protein binding is low (5%), ce
11、rebrospinal fluid concentrations are 20% of serum concentrations. Eliminated by glomerular filtration and tubular secretion. Should be taken on an empty stomach. Anti-HIV activity of ddI is potentiated by hydroxyurea(羟基脲) due to a depletion of intracellular pools of dATP, so two agents is administer
12、ed in combination.,Adverse effects: Dose-dependent pancreatitis Painful peripheral distal neuropathy Diarrhea Hepatitis Esophageal ulceration(食管溃疡) Cardiomyopathy Central nervous system toxicity (headach, irritability, insomnia),Nonnucleoside reverse transcriptase inhibitors,Including delavirdine, n
13、evirapine, efavirenz. Bind directly to a site on the viral reverse transcriptase that is near to but distinct from the binding site of the NRTIs. Neither compete with nucleoside triphosphates nor require phosphorylation to be active. The binding to the enzymes active site results in blockade of RNA-
14、 and DNA-dependent DNA polymerase activities.,Specific activity against HIV-1. Cross-resistance among this class of agents. The rapid emergence of resistance prohibits monotherapy with any of the NNRTIs. No cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors. Oral bioavailab
15、ility is high. Metabolized by the CYP3A P450 isoform, excreted in the urine. Adverse effects: skin rash,Protease inhibitors,Including ritonavir, nelfinavir, saquinavir, indinavir and amprenavir.,Combination therapy with other agents is recommended to avoid emergence of resistance, because of specifi
16、c genotypic alterations. Adverse effect: Syndrome of altered body fat distribution (buffalo hump and truncal obesity, with facial and peripheral atrophy) Insulin resistance Hyperlipidemia(高脂血症),Others Antiviral Agents,Including: Nucleoside antiviral agents Nonnucleoside antiviral agents Immune enhancement agent Mechanism of action: Compete the receptors, eg: Heparin, Polysaccharide Block viral adsorption to and penetration into host cells and uncoating of viral nucleic acid, eg: amantadine Block viral biosynthesis, eg: idoxuridine Enhance the host immune activity, eg: interferon,
