Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

• Published in: International journal of molecular sciences Vol. 24; no. 9; p. 7938
• Main Author: Ji, Cheng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.04.2023; MDPI
• Subjects: Acquired immune deficiency syndrome; AIDS; Alcohol use; Anti-HIV agents; Antiviral agents; Antiviral Agents - adverse effects; Antiviral Agents - chemistry; Antiviral drugs; Apolipoproteins; Atazanavir; Chemical and Drug Induced Liver Injury; Coronaviruses; COVID-19; Darunavir; Drug therapy; Fosamprenavir; Health aspects; HIV; HIV (Viruses); HIV infection; HIV Infections - complications; HIV Infections - drug therapy; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Humans; Infection; Insulin; Insulin resistance; Isoenzymes; Kinases; Liver; Protease Inhibitors - pharmacology; Proteases; Reactive oxygen species; Review; SARS-CoV-2; unfolded protein response; liver disease; anti-AIDS/COVID-19 drugs; ER/Golgi stress; alcohol use disorder (AUD); side effects; substance use disorders (SUD); safer drug design
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24097938

Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.