Antiviral Agents

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Antiviral Agents

• GAO Fen-Fei

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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.

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Research in Antiviral Chemotherapy

• In the early 1950s, IdUR and Trifluorothymidine(??
  ??????)
• In the mid 1970s, Adenine arabinoside
  (Vidarabine,ara-A,????)
• In the late 1970s, Acyclovir (????)
• With the appearance of AIDS epidemic in the
  1990s, Inhibitor reverse transcriptase or the
  protease

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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

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HIV???
??RNA
?????DNA
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HIV???
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NRTIs
NNRTIs
Drugs
PIs
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reverse transcriptase
Incorporated into host genome
HIV integrase
double helix DNA
ViralRNA
transcription translation
Final structural proteins
HIV protease
Polyproteins
NRTIs
NNRTIs
Drugs
PIs
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Nucleoside Reverse Transcriptase Inhibitors

• Derivatives of Pyramine AZT, ddC, d4T, 3TC
• Derivatives of Purine ddI, ABC

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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 form
• Most have activity against HIV-2 as well as HIV-1.

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Zidovudine

• Azidothymidine (??????), 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.

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• Decrease the rate of clinical disease progression
  and prolong survival.
• Treatment HIV-associated dementia(??) and
  thrombocytopenia(?????).
• Reduce the rate of vertical (mother-to-newborn)
  transmission of HIV.
• Adverse effect myelosuppression(????) ? anemia
  or neutropenia gastrointestinal intolerance,
  headachs, insomnia(??)

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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.

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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-dependent.
• Plasma protein binding is negligible, mean
  cerebrospinal fluid concentrations are 55 of
  those of plasma.
• Excretion is by active tubular secretion and
  glomerular filtration.

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• Adverse effects
• Dose-limiting toxicity is a dose-related
  peripheral sensory neuropathy.
• Pancreatitis, arthralgias(???), elevation in
  serum aminotransferases(???).

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Didanosine (ddI)

• Synthetic analog of deoxyadenosine
• Plasma protein binding is low (lt5),
  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(???) due to a depletion of
  intracellular pools of dATP, so two agents is
  administered in combination.

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• Adverse effects
• Dose-dependent pancreatitis
• Painful peripheral distal neuropathy
• Diarrhea
• Hepatitis
• Esophageal ulceration(????)
• Cardiomyopathy
• Central nervous system toxicity (headach,
  irritability, insomnia)

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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 enzymes active site results
  in blockade of RNA- and DNA-dependent DNA
  polymerase activities.

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• 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

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Protease inhibitors

• Including ritonavir, nelfinavir, saquinavir,
  indinavir and amprenavir.

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• 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(????)

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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

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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

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Acyclovir (ACV)

• An acyclic guanosine derivative
• Pharmacological effects
• Against HSV-1 and HSV-2 and against
  varicella-zoster virus, Epstein-Barr virus and
  cytomegalovirus.

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• 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
  hosts 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

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• Resistance
• HSV or VZV alteration in either the viral
  thymidine kinase or the DNA polymerase ?
  resistance
• Cross-resistance to valacyclovir(????),
  famciclovir(????), and ganciclovir(????).
• Agents such as foscarnet(???), cidofovir(????),
  and trifluridine(????) do not require activation
  by viral thymidine kinase and thus have preserved
  activity against the most prevalent
  acyclovir-resistant strains.

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• 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.

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• 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

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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.

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Ganciclovir

• An acyclic guanosine(??) analog
• Against CMV is up to 100 times greater than that
  of acyclovir.
• Adverse reactions
• Myelosuppression(????), particularly
  neutropenia(?????????)

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Trifluridine(????)

• Trifluorothymidine(????????), Fluorinated
  pyrimidine nucleoside.
• Against HSV-1, HSV-2, vaccinia(??), and some
  adenoviruses(???).
• Incorporation of trifluridine triphosphate into
  both viral and cellular DNA prevents its systemic
  use.
• Therapy for keratoconjunctivitis(?????) 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.

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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.

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• Topical application for acute keratoconjunctivitis
  (?????), superficial keratitis(?????), 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.

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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.

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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(?????),
  respiratory syncytial virus(???????),
  paramyxoviruses(????), HCV(????), and HIV-1.

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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
  food-dependent.
• The majority of lamivudine is eliminated
  unchanged in the urine.

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Nonnucleoside Antiviral Agents

• Including
• Rimantadine and Amantadine
• Foscarnet

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Rimantadine and Amantadine

• Rimantadine is Amantadines amethyl 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)

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Foscarnet

• An inorganic(???) pyrophosphate(????) 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.

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• Poor oral bioavailability. Only intravenous
  administration.
• CMV retinitis(????) and acyclovir-resistant HSV
  infection.

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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.

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• Classified on the basis of the cell types from
  which they were derived
• Interferon a(type ?)leukocyte(???)
• Interferon ß(type ?)fibroblast(?????)
• Interferon ?(type ?)immune cell(????)

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• Three known enzymes are induced by interferons
• A protein kinase that leads to phosphorylation of
  elongation factor 2, resulting in inhibition of
  peptide chain initiation
• Oligoisoadenylate synthase (??????), which leads
  to activation of a ribonuclease (RNA?) and
  degradation of viral mRNA
• A phosphodiesterase (?????) that can degrade the
  terminal nucleotides of tRNA, inhibiting peptide
  elongation.

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• Treatment of chronic hepatitis C, AIDS-associated
  Kaposis sarcoma, hairy cell leukemia, and
  chronic myelogenous leukemia (??????), malignant
  melanoma (??????), condylomata acuminata (????),
  relapsing multiple sclerosis (?????????).
• Toxicities neutropenia(?????????), anemia,
  thrombocytopenia(?????), elevated
  aminotransferase levels(?????), flu-like symptoms
  (including fever, chills, headache, myalgias??,
  fatigue??)

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Polyinosinic Polycytidylic Acid

• Synthetic doublestranded RNA (dsRNA).
• Inducer of interferon.
• Immune enhancement and broad spectrum antiviral
  effects.
• allergic reaction.