Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41

Abstract

Background The transmembrane subunit of the HIV envelope protein, gp41 is a vulnerable target to inhibit HIV entry. There is one fusion inhibitor T20 (brand name: Fuzeon, generic name: enfuvirtide) available by prescription. However, it has several drawbacks such as a high level of development of drug resistance, a short-half life in vivo, rapid renal clearance, low oral bioavailability, and it is only used as a salvage therapy. Therefore, investigators have been studying a variety of different modalities to attempt to overcome these limitations. Methods Comprehensive literature searches were performed on HIV gp41, inhibition mechanisms, and inhibitors. The latest structural information was collected, and multiple inhibition strategies targeting gp41 were reviewed. Results Many of the recent advances in inhibitors were peptide-based. Several creative modification strategies have also been performed to improve inhibitory efficacy of peptides and to overcome the drawbacks of T20 treatment. Small compounds have also been an area of intense research. There is a wide variety in development from those identified by virtual screens targeting specific regions of the protein to natural products. Finally, broadly neutralizing antibodies have also been important area of research. The inaccessible nature of the target regions for antibodies is a challenge, however, extensive efforts to develop better neutralizing antibodies are ongoing. Conclusion The fusogenic protein, gp41 has been extensively studied as a promising target to inhibit membrane fusion between the virus and target cells. At the same time, it is a challenging target because the vulnerable conformations of the protein are exposed only transiently. However, advances in biochemical, biophysical, structural, and immunological studies are coming together to move the field closer to an understanding of gp41 structure and function that will lead to the development of novel drugs and vaccines.

Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets

“…91–93 The glycoprotein gp41 is a viral fusion protein expressed on the surface of the HIV virion which, together with gp120, mediates the recognition and fusion of the host and HIV membranes, leading to infection. 94,95 Inhibition of gp41 activity is clinically recognized to inhibit HIV infection.…”

“…94,95 Inhibition of gp41 activity is clinically recognized to inhibit HIV infection. 96 Small molecule inhibitors of gp41 have been shown to work in vitro , but lack clinical endorsement 60,91–93 In this application, we used de novo DOCK to build a large ensemble of new molecules designed to target the gp41 N-helical hydrophobic pocket (PDB: 1AIK), 59 and to mimic key interactions of the native C-helical binding partner motif termed “WWDI”. The same generic fragment libraries, torsion environments, and protocol (15 anchors, standard sampling) used for the 57 systems discussed in the previous section were also employed here.…”

Computational identification of self-inhibitory peptides from white spot syndrome virus envelope protein VP28

“…Peptides derived from envelope proteins are supposed to be able to mimic the modes of binding of its original domain to its specific partner protein, thus, they may serve as potential inhibitors to disrupt the protein-protein interactions in membrane fusion mediated by the envelope proteins (Xu et al, 2012). Many peptides have exhibited good performance against the corresponding viruses, including dengue virus (Costin et al, 2010;Schmidt et al, 2010), SARS coronavirus (Ho et al, 2006), and most notably, HIV-1 (Yi et al, 2016), and the main feature of them is the high hydrophobicity, some computational tools based on this feature have been proved to be useful in identifying potential inhibitory peptides (Xu et al, 2012;Koehler et al, 2013;Spence et al, 2014).…”

“…Since entry into the cell is the first step for the initiation, dissemination, and maintenance of virus infection, blocking this process will have a significant inhibitory effect. Considering the vital roles in the initial steps of the viral infectious cycle such as recognition and attachment, envelope proteins have become the ideal targets for antiviral strategies development (Yi et al, 2016;Dinesh et al, 2017;Priya et al, 2018;de Wispelaere et al, 2018), among which, design of antiviral peptides (AVPs) has lately regained interest following pioneering advancements in technology (Chew et al, 2017). By using this approach, peptides derived from several viruses have been designed and exhibited significant self-inhibitory activity (Ho et al, 2006;Costin et al, 2010;Schmidt et al, 2010;Xu et al, 2012;Koehler et al, 2013;Spence et al, 2014).…”

Structure-based identification of inhibitors targeting obstruction of the HIVgp41 N-heptad repeat trimer

“…4–6 Focusing on targeting gp41, there are several inhibitory strategies many of which focus on the pre-hairpin intermediate. 7–11 In particular, C-heptad repeat (CHR) derived inhibitors, such as the FDA approved peptide drug T20 (Fuzeon), bind the gp41 intermediate, which obstructs association of the native outer CHR helices. This binding event prevents formation of the six-helix bundle required for viral entry.…”