HIV-1 Integrase Inhibitors: A Review of Their Chemical Development

Abstract

Highly active antiretroviral therapy (HAART) significantly decreases plasma viral load, increases CD4+ T-cell counts in HIV-1-infected patients and has reduced progression to AIDS in developed countries. However, adverse side effects, and emergence of drug resistance, mean there is still a demand for new anti-HIV agents. The HIV integrase (IN) is a target that has been the focus of rational drug design over the past decade. In 2007, raltegravir was the first IN inhibitor approved by the US Food and Drug Administration for antiretroviral combination therapy, while another IN inhibitor, elvitegravir, is currently in Phase III clinical trials. This article reviews the development and resistance profiling of small molecule HIV-1 IN inhibitors.

Development of Elvitegravir Resistance and Linkage of Integrase Inhibitor Mutations with Protease and Reverse Transcriptase Resistance Mutations

“…HIV-1 integrase inhibitors (INI) are a relatively new class of antiretroviral (ARV) medications that function by preventing strand displacement and integration of the HIV-1 provirus into the host cell genome [1]. Raltegravir (RAL) was the first US FDA approved INI, and has demonstrated significant antiviral activity in ARV experienced and naïve patients when combined with other ARV classes [2], [3].…”

From base pair to bedside: molecular simulation and the translation of genomics to personalized medicine

“…Until recently only partial structures of IN were available; one of these including the inhibitor 5CITEP was used by Schames et al32 as the basis for a set of MD simulations which revealed a novel binding trench adjacent to the active site. Matching a library of compounds to this new IN conformation using docking techniques that account for receptor flexibility led directly to the design and synthesis of what is now called the drug raltegravir 33. This was achieved despite the partial structure having poorly resolved loops close to the active site and the absence of bound DNA, both of which are believed to form important parts of the binding site.…”

Recombinant rabbit single‐chain antibodies bind to the catalytic and C‐terminal domains of HIV‐1 integrase protein and strongly inhibit HIV‐1 replication

“…The HIV-1 integrase (IN) protein is currently the focus of an intense research effort to develop improved anti-HIV-1 drugs [9–11]. This enzyme catalyzes the integration of the HIV genome into the chromosome of the host cell, arguably the most insidious step in the infection process [12].…”

“…During the past 10 years, several IN inhibitors have been developed to block the integration step [9–11],[25]. However, progress in the development of IN inhibitors has been slow; most of these compounds have not met the minimum standards required to be defined as lead molecules in the search for clinically useful applications or have been toxic in cell cultures [9–11],[25].…”

“…However, progress in the development of IN inhibitors has been slow; most of these compounds have not met the minimum standards required to be defined as lead molecules in the search for clinically useful applications or have been toxic in cell cultures [9–11],[25]. Recently, the first IN inhibitor, MK-0518 (ral-tegravir), received US Food and Drug Administration approval and entered clinical use [26].…”