Pharmacology of current and promising nucleosides for the treatment of human immunodeficiency viruses

• Type of Material: Article
• Authors: Raymond Schinazi, Emory University; Brenda I. Hernandez-Santiago, Emory University; Selwyn Hurwitz, Emory University
• Language: English
• Date: 2006-09-01
• Publisher: ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2006 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.antiviral.2006.03.012
• Title of Journal or Parent Work: ANTIVIRAL RESEARCH
• Volume: 71
• Issue: 2-3
• Start Page: 322
• End Page: 334
• Grant/Funding Information: The preparation of this review was supported by the NIH grant 5R37-AI-41980, 2R37-AI-25899, Emory’s CFAR (5P30-AI-50409) and the Department of Veterans Affairs. RFS is entitled to future royalties derived from the sale of products related to the research described in this paper and is a founder of Pharmasset Inc and RFS Pharma LLC.
• Keywords: Science & Technology; nucleoside analogs; HIV-INFECTED ADULTS; antiviral agents; MITOCHONDRIAL-DNA; TENOFOVIR DISOPROXIL FUMARATE; IN-VITRO; WILD-TYPE; Life Sciences & Biomedicine; Pharmacology & Pharmacy; DIOXOLANE GUANOSINE; BLOOD MONONUCLEAR-CELLS; HIV; Virology; pharmacology; REVERSE-TRANSCRIPTASE INHIBITORS; POPULATION PHARMACOKINETICS; HEPATITIS-B-VIRUS
• Research Categories: Health Sciences, Pharmacology; Biology, Virology; Health Sciences, Public Health

Abstract

Nucleoside antiretroviral agents are chiral small molecules that have distinct advantages compared to other classes including long intracellular half-lives, low protein binding, sustained antiviral response when a dose is missed, and ease of chemical manufacture. They mimic natural nucleosides and target a unique but complex viral polymerase that is essential for viral replication. They remain the cornerstone of highly active antiretroviral therapy (HAART) and are usually combined with non-nucleoside reverese transcriptase and protease inhibitors to provide powerful antiviral responses to prevent or delay the emergence of drug-resistant human immunodeficiency virus (HIV). The pharmacological and virological properties of a selected group of nucleoside analogs are described. Some of the newer nucleoside analogs have a high genetic barrier to resistance development. The lessons learned are that each nucleoside analog should be treated as a unique molecule since any structural modification, including a change in the enantiomeric form, can affect metabolism, pharmacokinetics, efficacy, toxicity and resistance profile.