Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors.
Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.
Serrao
Erik
E
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA 90089, USA. eserrao@usc.edu
Odde
Srinivas
S
Ramkumar
Kavya
K
Neamati
Nouri
N
D000998:Antiviral Agents / Q000494:pharmacology*; D055808:Drug Discovery / Q000639:trends; D015658:HIV Infections / Q000188:drug therapy; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D011760:Pyrrolidinones / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D000068898:Raltegravir Potassium
D000998:Antiviral Agents; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D015363:Quinolones; D000068898:Raltegravir Potassium; C509700:elvitegravir; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1