Abstract
Virus-cell fusion is the primary means by which the human immunodeficiency virus-1 (HIV) delivers its genetic material into the human T-cell host. Fusion is mediated in large part by the viral glycoprotein 41 (gp41) which advances through four distinct conformational states: (i) native, (ii) pre-hairpin intermediate, (iii) fusion active (fusogenic), and (iv) post-fusion. The pre-hairpin intermediate is a particularly attractive step for therapeutic intervention given that gp41 N-terminal heptad repeat (NHR) and C‑terminal heptad repeat (CHR) domains are transiently exposed prior to the formation of a six-helix bundle required for fusion. Most peptide-based inhibitors, including the FDA‑approved drug T20, target the intermediate and there are significant efforts to develop small molecule alternatives. Here, we review current approaches to studying interactions of inhibitors with gp41 with an emphasis on atomic-level computer modeling methods including molecular dynamics, free energy analysis, and docking. Atomistic modeling yields a unique level of structural and energetic detail, complementary to experimental approaches, which will be important for the design of improved next generation anti-HIV drugs.
Highlights
Infection with human immunodeficiency virus-1 (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS) [1,2], is a significant global health threat
Organization (WHO) estimated that in 2010, 1.8 million deaths could be attributed to AIDS-related causes, and that approximately 34 million people worldwide were living with an HIV infection [3]
The number of AIDS-related deaths has been on the decline since 2005 due to significant advances in antiretroviral therapies which were developed in large part using structure-based drug design [4]
Summary
Infection with human immunodeficiency virus-1 (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS) [1,2], is a significant global health threat. The number of AIDS-related deaths has been on the decline since 2005 due to significant advances in antiretroviral therapies which were developed in large part using structure-based drug design [4]. (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs), (iii) protease inhibitors (PIs), (iv) fusion inhibitors, (v) entry inhibitors, and (vi) integrase strand transfer inhibitors [5] Despite their successes, drug-resistant HIV mutants commonly arise during long-term clinical use of these therapies [6,7]. Many of these drugs are accompanied by adverse side effects, are expensive to produce, or, in the case of peptide fusion inhibitors, require injection to administer. Fusion of the HIV outer envelope and the host cell membrane is an essential event for virus infection and proliferation. The focus of this review is the structural biology of gp with special emphasis on the extracellular domain, and the link between available experimental models of the protein structure and atomistic computational techniques which exploit those models to aid in drug discovery
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