Update on the development of HIV entry inhibitors

Abstract

HIV fusion and entry are two steps in the viral lifecycle that can be targeted by several classes of antiviral drugs. The discovery of chemokines focused the attention on cellular co-receptors used by the virus for entering cells, and on the various steps of such processes that are subject to interactions with small molecules. Intense research has led to a wide range of effective compounds that are able to inhibit these initial steps of viral replication. All steps in the process of HIV entry into the cell may be targeted by specific compounds, grouped into three main classes (attachment inhibitors, co-receptor binding inhibitors and fusion inhibitors), which may be developed as novel antiretrovirals. Thus, several inhibitors of the gp120–CD4 interaction have been discovered (e.g., zintevir and BMS-378806). Small molecule chemokine receptor antagonists acting as HIV entry inhibitors have also been described recently, including those which interact with both the CXCR4 co-receptor (e.g., AMD3100, AMD3465, ALX40-4C, T22, T134 and T140) and CCR5 co-receptor antagonists (TAK-779, TAK-220, E913, AK-602 and NSC 651016 in clinical trials). Recently, a third family of antivirals started to be used clinically (in addition to reverse transcriptase and protease inhibitors), with the advent of enfuvirtide (T20), the first fusion inhibitor to be approved as an anti-HIV agent. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, thus offering the rationale for their combination in therapies for HIV-infected individuals. Many HIV entry and fusion inhibitors are currently being investigated in controlled clinical trials, and a number of them are bioavailable as oral formulations. In 2007, the US FDA approved maraviroc as an anti-HIV agent. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin. Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. Furthermore, in October 2007, the FDA announced the approval of raltegravir for the treatment of HIV-1 infection as part of combination antiretroviral therapy in treatment-experienced patients with evidence of HIV-1 replication despite optimized background antiretroviral therapy. At present, raltegravir is the only drug in the integrase inhibitor class approved for clinical use. With the approval of raltegravir, oral agents targeting all three constitutive viral enzymes, reverse transcriptase, protease and integrase, are now represented in FDA-approved therapies.