HIV

HIV

HIV is short for Human immunodeficiency virus, which is a member of the genus lentivirus, part of the family retroviridae. Two type of HIV have been characterized: HIV-1 and HIV-2. HIV-1 (Human immunodeficiency virus type 1) is a retrovirus that may produce an acute, usually self-limited mononucleosis-like syndrome but more inevitably causes a broad array of progressive clinical manifestations, widely known as the acquired immunodeficiency syndrome (AIDS). HIV-2 (Human immunodeficiency virus type 2) causes a similar but far less widespread infection and a generally more indolent chronic disease.

Introduction

An estimated 34 million people are infected worldwide with human immuno-deficiency virus (HIV), the etiologic cause of acquired immunodeficiency syndrome (AIDS). The AIDS epidemic becomes more and more serious in the world. However, the successful development of a safe and effective HIV vaccine is still in the future. Therefore, research continues to focus on disease treatment by chemical anti-HIV agents.

Until now, 24 chemical entities and 9 compositions were approved in clinical. They consist of highly active antiretroviral therapy (HAART), protease inhibitor (PR), integrase inhibitor and virus entry inhibitor. On HAART and PR regimens, multiple drug therapies can lead to increased adverse effects and toxicities due to long-term use and drug-drug interactions. Only 3 chemical entities of the last two classes were approved.

Research progress

The progress that HIV entry into host cells involves at least three steps: (1) first, the attachment step.This step requires CD4 receptor binding; (2) second, co-receptor binding; (3) third, a fusion process, in which HIV fuse with target cellular membrane. The envelope glycoprotein (Env) on the surface of virus mediates the entry progress. Virus can attach to target cells, followed by specific binding of HIV gp120 to the CD4 receptor on the cellular membrane. This binding induces a conformational change in gp120 that opens up a high-affinity binding site located within the third variable loop (V3) and surrounding surfaces for the chemokine co-receptors (primarily CCRS and CXCR4). Co-receptor binding results in further conformational rearrangements of gp120 that expose the fusion-peptide domain of gp41.The heptad repeat (HR) regions, HR1 and HR2 of the three subunits of gp41,fold and pack into a six-helix bundle, which brings the viral and cell membranes into juxtaposition and creates pores in the target cell membrane, enabling the release of viral capsid into the cytoplasm.

The-process-of-HIV-infecting-CD4-T-zelle

Figure 1 The process of HIV infecting CD4+T-zelle

From the virus fuse target cells progress, different entry inhibitors can be divided into 3 classes: (1) first, gp120-CD4 binding inhibitors, (2) second, co-receptor binding inhibitors, and (3) fusion inhibitors, especially inhibiting gp41 core structure formation. Each step of this sequential entry process has been suggested as a potential target for developing anti-HIV 1 drugs. Among HIV entry into host cells progress, an attachment step that gp120 binds to CD4 was the first step. HIV entry inhibitors targeting this first step can theoretically reduce the harmfulness to human.

The binding of HIV-1 gp120 to the cellular receptor CD4 is critical for HIV-1 entry into cells and has also been suggested as a potential target for developing anti-HIV 1 therapy. HIV entry inhibitors that block gp120-CD4 interactions mainly consist of two types of compounds, large molecular compounds and small molecular compounds. Large molecular inhibitors were CD4 and neutralization antibodies and small molecular inhibitors consist of BMS-378806 and NBD-556 analogues. The Phe43 cavity has been suggested as the putative binding site of BMS-378806 and NBD-556, two potent entry inhibitors. This discovery is fundamentally important and raises hopes that small molecule inhibitors are capable of disrupting protein-protein interactions when targeted to the so-called "hot spots" such as the cavity.

Among these targets, viral entry is one of the most promising for HIV drug. HIV entry inhibitor, although only 2 chemical entities were approved, was found effective for the virus resistant to HARRT and PR therapy. Enfuvirtide (T-20), which is a HIV fusion inhibitor, was the first drug with a target other than RT and PR to be approved by the US FDA. The success of Enfuvirtide and Maraviroc validates the clinical application of viral entry inhibitors as a new class of antiretroviral drugs. Continued effort in discovering new HIV inhibitors, especially potent and orally bioavailable small molecules, is still needed.

References:

1. Balzarini, J. & Van Damme, L. Microbicide drug candidates to prevent HIV infection. Lancet 369, 787-797, doi:10.1016/s0140-6736(07)60202-5 (2007).

2. Haynes, B. F. & Burton, D. R. HIV Developing an HIV vaccine What are the paths and obstacles to a practical vaccine? Science 355, 1129-1130, doi:10.1126/science.aan0662 (2017).

3. Zhu, P. et al. Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature 441, 847-852, doi:10.1038/nature04817 (2006).

4. Pancera, M. et al. Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529. Nature Chemical Biology 13, 1115-+, doi:10.1038/nchembio.2460 (2017).

5. Kaushik-Basu, N. & Harris, D. Peptide inhibition of HIV-1 - Current status and future potential. Biodrugs 22, 161-175, doi:10.2165/00063030-200822030-00003 (2008).

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