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.