Antiviral Agents in Pharmaceutical Chemistry

Unit Outcomes

  • Trace the biosynthetic pathways involved in the action of antiviral agents.
  • Classify and characterize the types of antiviral agents and enumerate drugs under each type.
  • Identify and interpret structure-activity relationships of antiviral agents.
  • Apply principles of medicinal chemistry in the synthesis and characterization of organic medicinal compounds.

Unit Outline

  • Topics:
    • Classification and characterization of antiviral agents.
    • Structure-activity relationship of antiviral agents.
Checklist
  • Read course outcomes and guide prior to class.
  • Participate in discussions and online platforms (e.g., Canvas).
  • Watch related instructional videos.

Overview of Viruses

  • Definition: Smallest self-replicating organisms, categorized as parasitic.
  • Structure:
    • Nucleic Acid Core: Either DNA or RNA along with virus-specific enzymes.
    • Capsid: Protein coat surrounding the nucleic acid core, sometimes with an outer lipid envelope.
    • Complete viral particle is referred to as a virion.

Productive Infection

  • Definition: Infection resulting in production of more viruses than initiated the infection.
  • Burst Size: Number of infectious viruses produced per infected cell.

Classification of Viruses

  • Baltimore Classification Scheme:
    • DNA Viruses:
    • Herpesvirus
    • Papovavirus
    • Adenovirus
    • Hepadnavirus
    • Poxvirus
    • Parvovirus
    • Most remaining are RNA viruses.

Infectious Process for Viruses (Steps):

  1. Adsorption
  2. Entry
  3. Uncoating
  4. Transcription
  5. Translation
  6. Assembly
  7. Release

Viral Cell Tropism

  • Examples:
    • HIV: CD4+ T lymphocytes, macrophages
    • Influenza A: Respiratory epithelium
    • Hepatitis viruses: Liver cells (hepatocytes)
    • Common cold: Nasal epithelium.

Main Targets of Antiviral Agents

  • Primary Targets: Viral enzymes including:
    • Nucleic Acid Polymerases
    • DNA-dependent DNA polymerase (DNA viruses).
    • RNA-dependent RNA polymerase (RNA viruses).
    • RNA-dependent DNA polymerase (for retroviruses).
    • Proteases and Integrases involved in viral replication.
    • Neuraminidases (orthomyxoviruses).

Mechanism of Action of Antivirals

  • Entry Inhibitors: Target cell receptor sites to prevent viral entry.
  • Uncoating Inhibitors: Block the uncoating process of the viral shell (e.g., amantadine).
  • Synthesis Inhibitors:
    • RNA synthesis inhibition (interferon, ribavirin).
    • Genome replication inhibition via polymerase or reverse transcriptase inhibitors (nucleoside/nucleotide analogs).
    • Assembly inhibition (protease inhibitors).
    • Release inhibition through neuraminidase inhibitors.
Examples of Antiviral Agents
  • Amantadine/Rimantadine:
    • Inhibition of uncoating, effective only for influenza A virus.
  • Neuraminidase Inhibitors:
    • Zanamivir and Oseltamivir for influenza types A and B, effective before and after exposure.
    • Oseltamivir is orally efficacious due to its ethyl ester modification.
  • Interferon: Broad-spectrum antiviral agent; produced naturally in the body, effective against various RNA and DNA viruses.
  • Nucleoside Antimetabolites:
    • Idoxuridine: Used in herpes infection treatment.
    • Acyclovir: An acyclic guanosine derivative effective against HSV and VZV, mechanism involves chain termination during DNA replication.
    • Ganciclovir: More potent against CMV than acyclovir, with specific bioavailability concerns.
Reverse Transcriptase Inhibitors (RTIs)
  • NRTIs:
    • Examples include Zidovudine (AZT), Didanosine (ddI), Zalcitabine (ddC), Stavudine (d4T), and Lamivudine (3TC).
  • NNRTIs: Non-nucleoside analogues that bind reversely and inhibit viral reverse transcriptase.
  • Integrase Inhibitors:
    • Prevents viral DNA from integrating into the host genome (e.g., Dolutegravir).
  • Protease Inhibitors:
    • Landscape of drugs targeting the protease enzyme critical for viral maturation (e.g., Ritonavir).
Adverse Effects of Antiviral Agents
  • Common adverse effects for several antivirals include nausea, diarrhea, myelosuppression, peripheral neuropathy, and possible renal impairment due to different agents.

Recent Developments in Antiviral Therapy

  • Notable mentions include Remdesivir for COVID-19,
    and various combinations aimed at providing effective treatment regimens for chronic infections, particularly for HIV and Hepatitis.