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 Chemotherapy

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 th

e 1990s, Inhibitor reverse transcriptase or the protease

Antiretroviral (Anti-HIV) Agents

The first 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 agent

s (cocktail therapy) → enhancing potency and delaying resistance

病毒RNA

互补双螺旋 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

NRTIsNNRTIs

PIs

ViralRNA

double helix DNA

Incorporated into host genome

reverse transcriptase

HIV integrase

transcriptiontranslation

Polyproteins

Final structural proteins

HIV protease

Drugs

NRTIsNNRTIs

PIs

Nucleoside Reverse Transcriptase Inhibitors

Derivatives of Pyramine: AZT, ddC, d4T, 3TC

Derivatives of Purine: ddI, ABC

Mechanism of Action

① Competitive inhibition of HIV-1 reverse transcriptase;

② Incorporated into the growing viral DNA chain → cause termination

Drugs requires intracytoplasmic activation--- phosphorylation → triphosphate form

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 t

o most body tissues and fluids, including the cerebrospinal fluid.

Eliminated primarily by renal excretion following glucuronidation 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; gastrointestinal intolerance, headachs, insomnia(失眠 )

Zalcitabine (ddC)

Cytosine analog Anti-HIV-1 Zalcitabine + Zidovudine + one protease inhi

bitor Long intracellular half-life of 10hs. Dose-dependent peripheral neuropathy. Co

ntraindication to use with other drugs that may cause neuropathy.

Stavudine

Thymidne 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-dep

endent. Plasma protein binding is negligible, mean cerebro

spinal fluid concentrations are 55% of those of plasma.

Excretion is by active tubular secretion and glomerular filtration.

Adverse effects:• Dose-limiting toxicity is a dose-related periphera

l sensory neuropathy.• Pancreatitis, arthralgias(关节痛 ), elevation in s

erum aminotransferases(转氨酶 ).

Didanosine (ddI)

Synthetic analog of deoxyadenosine Plasma protein binding is low (<5%), cerebrospinal

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 hydroxyur

ea(羟基脲 ) due to a depletion of intracellular pools of dATP, so two agents is administered 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, irritab

ility, insomnia)

Nonnucleoside reverse transcriptase inhibitors

Including delavirdine, nevirapine, efavirenz. Bind directly to a site on the viral reverse transcript

ase 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 enzyme’s active site results in blockade of RNA- 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 a

nd the NRTIs or the protease inhibitors. Oral bioavailability is high. Metabolized by the CYP3A P450 isoform, ex

creted in the urine. Adverse effects: skin rash

Protease inhibitors

Including ritonavir, nelfinavir, saquinavir, indinavir and amprenavir.

Gag and Gag-Polgene

Polyproteins,Immature budding particles

translate

Final structural proteins,Mature virioncore

protease

Combination therapy with other agents is recommended to avoid emergence of resistance, because of specific genotypic alterations.

Adverse effect: • Syndrome of altered body fat distribution (buffal

o 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

Nucleoside Antiviral Agents

Including Purine-nucleoside and Pyrimidine-nucleoside

Drugs requires intracytoplasmic activation--- phosphorylation → triphosphate form → competitive inhibition of viral DNA polymerase.

Incorporated into the growing viral DNA chain → cause termination

Acyclovir (ACV)

An acyclic guanosine derivative Pharmacological effects:

• Against HSV-1 and HSV-2 and against varicella-zoster virus, Epstein-Barr virus and cytomegalovirus.

Mechanism:• Three phosphorylation steps for activation.

First converted to the monophosphate derivative by the virus-specified thymidine kinase;（ selective activation）

Then to the di- and triphosphate compounds by host’s cellular enzymes.

• Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: Competitive inhibition of deoxyGTP for the viral DNA

polymerase, with binding to the DNA template as an irreversible complex;

Incorporation into the viral DNA → chain termination

Resistance• HSV or VZV alteration in either the viral thymidi

ne kinase or the DNA polymerase → resistance• Cross-resistance to valacyclovir(伐昔洛韦 ), famciclovir(泛昔洛韦 ), and ganciclovir(更昔洛韦 ).

• Agents such as foscarnet(膦甲酸 ), cidofovir(西多福韦 ), and trifluridine(三氟尿苷 ) do not require activation by viral thymidine kinase and thus have preserved activity against the most prevalent acyclovir-resistant strains.

Pharmacokinetics• Available in oral, intravenous, and topical formul

ations.• Oral bioavailability is 15-20%.• Plasma protein binding is low, diffuses into most

tissues and body fluids.• Cleared primarily by glomerular filtration and tub

ular secretion.

Clinical uses• Treatment of HSV infection —— first selection• Topical acyclovir is much less effective than oral therapy

for primary HSV infection. It is of no benefit in treating recurrences.

• VZV is less susceptible to acyclovir than HSV, high doses are required.

Adverse reactions• Nausea, diarrhea, headach• Intravenous infusion → renal insufficiency or neurologic

toxicity

Valacyclovir

The L-valyl ester of acyclovir It is rapidly converted to acyclovir after oral

administration, achieving serum levels three to five times greater than those achieved with oral acyclovir.

Ganciclovir

An acyclic guanosine(鸟苷 ) analog Against CMV is up to 100 times greater than

that of acyclovir. Adverse reactions:

• Myelosuppression(骨髓抑制 ), particularly neutropenia(嗜中性白血球减少症 )

Trifluridine(曲氟尿苷 )

Trifluorothymidine(三氟胸腺嘧啶核苷 ), Fluorinated pyrimidine nucleoside.

Against HSV-1, HSV-2, vaccinia(牛痘 ), and some adenoviruses(腺病毒 ).

Incorporation of trifluridine triphosphate into both viral and cellular DNA prevents its systemic use.

Therapy for keratoconjunctivitis(角膜结膜炎 ) and for recurrent epithelial keratitis due to HSV-1 and HSV-2.

Topical application, alone or in combination with interfon alfa, has been used successfully in treatment of acyclovir-resistant HSV infections.

Vidarabine, ara-A

Adenosine analog Against HSV, VZV, CMV, HBV and some RNA viru

ses. Phosporylated intracellular by host enzymes to for

m ara-ATP, incorporated into both viral and cellular DNA. → excessive toxicity

Rapidly metobolized to hypoxanthine arabinoside. Instability and toxicity limited its clinical utility.

Topical application for acute keratoconjunctivitis(角膜结膜炎 ), superficial keratitis(表皮角膜炎 ), and recurrent epithelial keratitis due to HSV-1 and HSV-2.

Intravenous for treatment of HSV encephalitis, neonatal herpes, and VZV infection in immunocompromised patients.

Idoxuridine

Competitive inhibition of thymidylic acid synthase → block DNA synthesis.

No effect on RNA virus. Only topical application because of its great

er side effects in systemic application. Treatment of ocular or dermal infections due

to herpesvirus or cowpox virus, especially acute epithelial keratitis due to herpesvirus.

Ribavirin (Virazole)

Guanosine analog. Phosphorylated intracellularly by host cell enzymes. Mechanism: to interfere with the synthesis of guanosine trip

hosphate, to inhibit capping of viral messenger RNA, and to inhibit the viral RNA-dependent RNA polymerase of certain viruses.

Ribavirin triphosphate inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza(副流感病毒 ), respiratory syncytial virus（呼吸道合胞病毒） , paramyxoviruses(副粘病毒 ), HCV（丙肝病毒） , and HIV-1.

Lamivudine (3TC)

Cytosine analog Against HIV-1, synergistic with a variety of antiretr

oviral nucleoside analogs, including zidovudine and stavudine.

Treatment of chronic hepatitis B infection. Oral bioavailability exceeds 80% and is not food-d

ependent. The majority of lamivudine is eliminated unchange

d in the urine.

Nonnucleoside Antiviral Agents

Including:• Rimantadine and Amantadine• Foscarnet

Rimantadine and Amantadine

Rimantadine is Amantadine’s α–methyl derivative. Cyclic amines. Inhibit uncoating of the viral RNA of influenza A wit

hin infected host cells. Prevention of influenza A virus infection. Reduce t

he duration of symptoms of influenza when administered within 48h of onset.

Adverse effects: gastrointestinal intolerance, central nervous system complaints (nervous, difficulty in concentrating, lightheadedness)

Foscarnet

An inorganic(无机的 ) pyrophosphate(焦磷酸盐 ) compound.

Inhibit viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly, without activation by phosphorylation.

Against HSV, VZV, CMV, EBV, HHV-6, HHV-8, and HIV.

Poor oral bioavailability. Only intravenous administration.

CMV retinitis(视网膜炎 ) and acyclovir-resistant HSV infection.

Immune Enhancement Agent

Interferon• a group of endogenous proteins that exert complex anti

viral, immunoregulatory, and antiproliferative activities through cellular metabolic processes involving synthesis of both RNA and protein.

• Although not specifically antiviral, they appear to function by causing elaboration of effector proteins in infected cells, resulting in inhibition of viral pentration and uncoating, mRNA synthesis and translating, or virion assembly and release.

Classified on the basis of the cell types from which they were derived:① Interferon α（ type Ⅰ）： leukocyte（白细胞）

② Interferon β（ type Ⅰ）： fibroblast（成纤维细胞）

③ Interferon γ（ type Ⅱ）： immune cell（免疫细胞）

Three known enzymes are induced by interferons:① A protein kinase that leads to phosphorylation of elong

ation factor 2, resulting in inhibition of peptide chain initiation;

② Oligoisoadenylate synthase (寡腺苷酸合酶 ), which leads to activation of a ribonuclease (RNA酶 ) and degradation of viral mRNA;

③ A phosphodiesterase (磷酸二酯酶 ) that can degrade the terminal nucleotides of tRNA, inhibiting peptide elongation.

Treatment of chronic hepatitis C, AIDS-associated Kaposi’s sarcoma, hairy cell leukemia, and chronic myelogenous leukemia (骨髓性白血病 ), malignant melanoma (恶性黑色素瘤 ), condylomata acuminata (尖锐湿疣 ), relapsing multiple sclerosis (复发的多发性硬化症 ).

Toxicities: neutropenia(嗜中性白血球减少症 ), anemia, thrombocytopenia(血小板减少 ), elevated aminotransferase levels(转氨酶升高 ), flu-like symptoms (including fever, chills, headache, myalgias 肌痛 , fatigue疲乏 )

Polyinosinic Polycytidylic Acid

Synthetic doublestranded RNA (dsRNA). Inducer of interferon. Immune enhancement and broad spectrum

antiviral effects. allergic reaction.