Transcript Antiviral Agents GAO Fen-Fei

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
the 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
agents (cocktail therapy) → enhancing potency
and delaying resistance
病毒
RNA
反转录酶
互补双螺
旋DNA
HIV整合酶
掺入宿主
基因组
转录
翻译
小分子功
能蛋白
NRTIs
Drugs
NNRTIs
PIs
HIV蛋白酶
多聚
蛋白
reverse
HIV integrase Incorporated
double
helix
Viral transcriptase
into host
DNA
RNA
genome
transcription
translation
Final
structural
proteins
NRTIs
Drugs
NNRTIs
PIs
HIV protease
Polyproteins
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
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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 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-tonewborn) 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
inhibitor
 Long intracellular half-life of 10hs.
 Dose-dependent peripheral neuropathy.
Contraindication 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 fooddependent.
 Plasma protein binding is negligible, mean
cerebrospinal 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
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%), 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
hydroxyurea(羟基脲) due to a depletion of
intracellular pools of dATP, so two agents is
administered in combination.
 Adverse effects:
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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, nevirapine, 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 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
and the NRTIs or the protease inhibitors.
 Oral bioavailability 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.
Gag and Gag-Pol translate
Polyproteins,
gene
Immature budding particles
protease
Final structural proteins,
Mature virioncore
 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
(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
Nucleoside Antiviral Agents
 Including Purine-nucleoside and Pyrimidinenucleoside
 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 varicellazoster 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
thymidine 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
formulations.
• Oral bioavailability is 15-20%.
• Plasma protein binding is low, diffuses into most
tissues and body fluids.
• Cleared primarily by glomerular filtration and
tubular 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 acyclovirresistant HSV infections.
Vidarabine, ara-A
 Adenosine analog
 Against HSV, VZV, CMV, HBV and some RNA
viruses.
 Phosporylated intracellular by host enzymes to
form 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
greater 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
triphosphate, 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
antiretroviral nucleoside analogs, including
zidovudine and stavudine.
 Treatment of chronic hepatitis B infection.
 Oral bioavailability exceeds 80% and is not fooddependent.
 The majority of lamivudine is eliminated
unchanged 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
within infected host cells.
 Prevention of influenza A virus infection. Reduce
the 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, HHV8, and HIV.
 Poor oral bioavailability. Only intravenous
administration.
 CMV retinitis(视网膜炎) and acyclovirresistant HSV infection.
Immune Enhancement Agent
 Interferon
• a group of endogenous proteins that exert complex
antiviral, 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）
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Three known enzymes are induced by
interferons:
① A protein kinase that leads to phosphorylation of
elongation 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.