Abstract
The hydrophobic pocket in the HIV-1 gp41 N-terminal heptad repeat (NHR) domain plays an important role in viral fusion and entry into the host cell, and serves as an attractive target for development of HIV-1 fusion/entry inhibitors. The peptide anti-HIV drug targeting gp41 NHR, T-20 (generic name: enfuvirtide; brand name: Fuzeon), was approved by the U.S. FDA in 2003 as the first HIV fusion/entry inhibitor for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, because T20 lacks the pocket-binding domain (PBD), it exhibits low anti-HIV-1 activity and short half-life. Therefore, several next-generation HIV fusion inhibitory peptides with PBD have been developed. They possess longer half-life and more potent antiviral activity against a broad spectrum of HIV-1 strains, including the T-20-resistant variants. Nonetheless, the clinical application of these peptides is still limited by the lack of oral availability and the high cost of production. Thus, development of small molecule compounds targeting the gp41 pocket with oral availability has been promoted. This review describes the main approaches for identification of HIV fusion/entry inhibitors targeting the gp41 pocket and summarizes the latest progress in developing these inhibitors as a new class of anti-HIV drugs.
Highlights
The acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) is still considered as one of the most life-threatening diseases
It has long been proven that combining antiretroviral agents with different mechanisms, such as reverse transcriptase inhibitors and protease inhibitors, which are the major components of highly active antiretroviral therapy (HAART), is the most effective therapeutic option to control of HIV type 1 (HIV-1) replication, especially against HIV-1 variants with multi-drug resistance [88]
The hydrophobic pocket in the exposed grooves on the gp41 N-terminal heptad repeat (NHR)-trimer plays an important role in stabilizing the gp41 6-HB and serves as an attractive target for identification of peptide- and small molecule compound-based HIV-1 fusion/entry inhibitors
Summary
The acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) is still considered as one of the most life-threatening diseases. Three CHR helices pack into the grooves on the NHR-trimer in an antiparallel manner to form a six-helix bundle (6-HB) core, which brings the viral and target cell membranes into close proximity for fusion (Figure 1B) [4,5,6,7]. FP, fusion peptide; NHR, N-terminal heptad repeat; PFD, pocket-forming domain; CHR, C-terminal heptad repeat; MPER, membrane-proximal external region; TM, transmembrane domain; and CP, cytoplasmic domain. The Env transmembrane subunit gp changes conformation by inserting the FP into the target cell membrane and forming 6-HB between the viral gp NHR and CHR regions, bringing the viral and target cell membranes into close proximity for fusion (C) The crystal structure of the gp41 6-HB and docking of NB-206 in the gp hydrophobic pocket cavity. The Env transmembrane subunit gp changes conformation by inserting the FP into the target cell membrane and forming 6-HB between the viral gp NHR and CHR regions, bringing the viral and target cell membranes into close proximity for fusion (C) The crystal structure of the gp41 6-HB and docking of NB-206 in the gp hydrophobic pocket cavity. (a) Side view of the gp41 6-HB core structure formed by the N-peptide, N36, and C-peptide, C34. (b) Stereo view of NB-206 docked in the hydrophobic pocket showing the possible interactions with the neighboring hydrophobic and charged residue K574. (c) Surface representation of the gp core (with one C-peptide removed) with bound ligand NB-206, which docks inside the cavity with the negatively charged COOH group pointing towards the positively charged side chain of K574
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