Antiviral Drugs for Respiratory Infections

Antiviral Drugs for Respiratory Viral Infections

• Antiviral drugs target respiratory viral infections like influenza, RSV, and COVID-19.
• Learning domains for pharmacy students include drug actions and drug substance.
• Learning objectives include the virus life cycle, where antiviral drugs work in the cycle, and antiviral drugs used in treating influenza, RSV, and COVID-19.
• Approximately 90 known virus families exist, growing by 2 each year. About 5,000 viruses have been described in detail, with most (~2,000) discovered in the 20th century.
• Viruses range in size from 5 to 300 nm.
• Common viral infections include the common cold (Rhinoviruses, Parainfluenza virus, Respiratory syncytial virus, Adenovirus), encephalitis and meningitis (JC virus, Measles, LCM virus, Arbovirus), Rabies, pharyngitis (Adenovirus), gingivostomatitis (Herpes simplex type 1), Epstein-Barr virus, Cytomegalovirus, cardiovascular infections (Coxsackie B virus), hepatitis (Hepatitis virus types A, B, C, D, E), skin infections (Varicella zoster virus, Human herpesvirus 6), smallpox, molluscum contagiosum, Human papillomavirus, Parvovirus B19, Rubella, Measles, Coxsackie A virus, sexually transmitted diseases (Herpes simplex type 2, Human papillomavirus, HIV), eye infections (Herpes simplex virus, Adenovirus, Cytomegalovirus), Parotitis (Mumps virus), pneumonia (Influenza virus, Types A and B, Parainfluenza virus, Respiratory syncytial virus, Adenovirus), SARS coronavirus, myelitis (Poliovirus, HTLV-I), gastroenteritis (Adenovirus, Rotavirus, Norovirus, Astrovirus, Coronavirus), and pancreatitis (Coxsackie B virus).
• Influenza, RSV, and SARS-CoV-2 diagrams show viral structure.
• Antiviral mechanisms: target viruses or cell pathways to prevent infection of new cells, block viral genome copying, mimic viral genetic material to cause errors, and stop viral protein activation with protease inhibitors.
• Antiviral agents affect viral attachment to host cells, virus-associated enzymes, transcription, translation, interference with viral regulatory proteins, glycosylation, phosphorylation, and assembly of viral proteins, and release from the cell surface membrane.
• Examples of antiviral drugs and their mechanisms of action are provided for influenza (oseltamivir, zanamivir, peramivir, baloxavir, marboxil), COVID-19 (remdesivir, nirmatrelvir + ritonavir, molnupiravir), and RSV (ribavirin).
• Nucleoside/Nucleotide RNA-dependent RNA polymerase (RdRp) inhibitors mimic natural nucleosides/nucleotides to interfere with viral replication. Antivirals for COVID-19 include Remdesivir and Molnupiravir.
• Oseltamivir phosphate (Tamiflu/Influenza) is an antiviral that binds to the HA protein of influenza viruses. Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease.

Antivirals and their mechanisms of action

• Antiviral actions include inhibiting viral attachment, endocytosis, fusion, uncoating, transcription, replication, assembly, and release.
• Specific examples are provided for influenza viruses (e.g., oseltamivir, zanamivir), COVID-19 (e.g., remdesivir, nirmatrelvir/ritonavir), and others.

SARS-CoV-2 Nucleoside Analogues

• Remdesivir (COVID-19) is a chain terminator, adenosine nucleoside analogue that inhibits replication of RNA viruses.
• Molnupiravir (COVID-19) is a prodrug cytidine nucleoside analogue that inhibits replication of RNA viruses.

Nirmatrelvir (part of Paxlovid) COVID-19

• Covalent protease inhibitor, hinders polyprotein processing.
• Demonstrated efficacy in 2018 for cat coronavirus.
• Ritonavir a protease inhibitor reduces metabolism of other drugs.

Influenza Virus Summary

• The documented viral life cycle (influenza) includes attachment, endocytosis, fusion, uncoating, transcription, RNA replication, protein synthesis, assembly, and release.
• There are a number of FDA approved antivirals like amantadine, rimantadine,MEDI8852, MHAA4549A,VIS-410 CT-P27, CR6261, CR8020,Fludase, Nitazoxanide, oseltamivir,zanamivir,peramivir, laninamivir,pimodivir, S-033188, AL-794, Baloxavir, Marboxil, Favipiravir.

Neuraminidase Inhibitors

• Designed to mimic the natural ligand (sialic acid) to inhibit NA (neuraminidase) activity.
• NA catalytically cleaves glycosidic bonds, facilitating viral exit from the host cell.

Summary

• Summary of different classes of antiviral drugs are provided in the notes.
• Details on the mechanisms of actions of these drugs are provided.
• Resistance levels to different drugs are given.
• Additional information includes data from September 2019.