Abstract
Small molecule inhibition of HIV fusion has been an elusive goal, despite years of effort by both pharmaceutical and academic laboratories. In this review, we will discuss the amphipathic properties of both peptide and small molecule inhibitors of gp41-mediated fusion. Many of the peptides and small molecules that have been developed target a large hydrophobic pocket situated within the grooves of the coiled coil, a potential hotspot for inhibiting the trimer of hairpin formation that accompanies fusion. Peptide studies reveal molecular properties required for effective inhibition, including elongated structure and lipophilic or amphiphilic nature. The characteristics of peptides that bind in this pocket provide features that should be considered in small molecule development. Additionally, a novel site for small molecule inhibition of fusion has recently been suggested, involving residues of the loop and fusion peptide. We will review the small molecule structures that have been developed, evidence pointing to their mechanism of action and strategies towards improving their affinity. The data points to the need for a strongly amphiphilic character of the inhibitors, possibly as a means to mediate the membrane - protein interaction that occurs in gp41 in addition to the protein – protein interaction that accompanies the fusion-activating conformational transition.
Keywords: HIV-1, gp41, inhibition, small molecules, amphiphilic, hydrophobic pocket, Small molecule inhibition, amphipathic properties, gp41-mediated fusion, affinity, membrane - protein interaction, fusion-activating conformational transition
Current Topics in Medicinal Chemistry
Title: Amphipathic Properties of HIV-1 gp41 Fusion Inhibitors
Volume: 11 Issue: 24
Author(s): Miriam Gochin and Guangyan Zhou
Affiliation:
Keywords: HIV-1, gp41, inhibition, small molecules, amphiphilic, hydrophobic pocket, Small molecule inhibition, amphipathic properties, gp41-mediated fusion, affinity, membrane - protein interaction, fusion-activating conformational transition
Abstract: Small molecule inhibition of HIV fusion has been an elusive goal, despite years of effort by both pharmaceutical and academic laboratories. In this review, we will discuss the amphipathic properties of both peptide and small molecule inhibitors of gp41-mediated fusion. Many of the peptides and small molecules that have been developed target a large hydrophobic pocket situated within the grooves of the coiled coil, a potential hotspot for inhibiting the trimer of hairpin formation that accompanies fusion. Peptide studies reveal molecular properties required for effective inhibition, including elongated structure and lipophilic or amphiphilic nature. The characteristics of peptides that bind in this pocket provide features that should be considered in small molecule development. Additionally, a novel site for small molecule inhibition of fusion has recently been suggested, involving residues of the loop and fusion peptide. We will review the small molecule structures that have been developed, evidence pointing to their mechanism of action and strategies towards improving their affinity. The data points to the need for a strongly amphiphilic character of the inhibitors, possibly as a means to mediate the membrane - protein interaction that occurs in gp41 in addition to the protein – protein interaction that accompanies the fusion-activating conformational transition.
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Cite this article as:
Gochin Miriam and Zhou Guangyan, Amphipathic Properties of HIV-1 gp41 Fusion Inhibitors, Current Topics in Medicinal Chemistry 2011; 11 (24) . https://dx.doi.org/10.2174/156802611798808488
DOI https://dx.doi.org/10.2174/156802611798808488 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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