title: 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.
  
  
  CONCLUSIONS
  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.
authors.forename: Hyun A
authors.initials: HA
authors.lastname: Yi
authors.forename: Brian C
authors.initials: BC
authors.lastname: Fochtman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rizzo
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, USA. jacobs2@buffalo.edu.
authors.forename: Amy
authors.initials: A
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery; D015483:HIV Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054730:Protein Interaction Domains and Motifs; D021122:Protein Subunits / Q000037:antagonists & inhibitors; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; D021122:Protein Subunits; C514787:gp41 protein, Human immunodeficiency virus 1