Raltegravir: molecular basis of its mechanism of action

Abstract

Integration of the HIV-1 viral DNA generated by reverse transcription of the RNA genome into the host cell chromosomes is a key step of viral replication, catalyzed by the viral integrase. In October 2007, the first integrase inhibitor, raltegravir, was approved for clinical use under the name of Isentress™. The results of the various clinical trials that have evaluated raltegravir have been very encouraging with regard to the immunological and virological efficacy and tolerance. However, as observed for other anti-retrovirals, specific resistance mutations have been identified in patients failing to respond to treatment with raltegravir. Although knowledge of the integrase structural biology remains fragmentary, the structures and modeling data available might provide relevant clues on the origin of the emergence of these resistance mutations. In this review, we describe the mechanism of action of this drug and the main data relating to its use in vivo, together with recent structural data important to our understanding of the origin of viral resistance.

Raltegravir flexibility and its impact on recognition by the HIV‐1 IN targets

“…The IN inhibitors were developed to block either the 3′‐P or the ST reaction (Pommier et al ., ; Cotelle, ; Semenova et al ., ). RAL, also known as Isentress™, is the first IN inhibitor approved for AIDS treatment (Marchand et al ., ), specifically inhibits the ST activity and was confirmed as IN ST inhibitor (INSTI), whereas the 3′‐P activity was inhibited only up to a certain concentration (Hazuda et al ., ; Mouscadet and Tchertanov, ). The potency of RAL has been described at the level of half maximal inhibitory concentration (IC 50 values) in cellular antiviral and recombinant enzyme assays, kinetic analysis and slow‐binding inhibition of IN‐catalyzed ST reaction (Hazuda et al ., ; Grobler et al ., ; Copeland et al ., ; Markowitz et al ., ; Dicker et al ., ; Garvey et al ., ; Hightower et al ., ).…”

Integrase inhibitors: Why do we need a new drug class for HIV therapy?

“…The molecular basis of the mechanism of action of an integrase inhibitor is provided by Jean-Francois Mouscadet and Luba Tchertanov in this supplement [2]. In principle, productive infection with HIV-1 requires three key steps in the viral replication.…”

1,2,4- and 1,3,4-Oxadiazoles as Scaffolds in the Development of Antiparasitic Agents

“…6 Raltegravir (9) is an HIV-1 integrase inhibitor, useful for the treatment of HIV infections. 7 by two atoms of carbon, two atoms of nitrogen and one atom of oxygen. They were firstly discovered in 1884 by Tiemann and Krüger, 8 then named furo [ab]diazoles.…”

“…Ketoconazole (5) is an important imidazolic antifungal that acts inhibiting the enzyme responsible for fungal ergosterol biosynthesis, 14α-demethylase. 4 Metronidazole (6) and benznidazole (7) are two antiprotozoal drugs acting through the generation of intracellular radical species which can damage both parasites' DNA and other cellular machinery. 5 The antibacterial fluoroquinolone ciprofloxacin (8) acts through the damage of bacterial DNA.…”