Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket.

Abstract

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell-cell fusion and infection.

• Authors: Yu Bai, Huifang Xue, Kun Wang, Lifeng Cai, Jiayin Qiu, Shuangyu Bi, Luhua Lai, Maosheng Cheng, Shuwen Liu, Keliang Liu
• Journal: Amino acids (Amino Acids) Vol. 44 Issue 2 Pg. 701-13 (Feb 2013) ISSN: 1438-2199 [Electronic] Austria
• PMID: 22961335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIV Envelope Protein gp41
• HIV Fusion Inhibitors

Topics

• Amino Acid Sequence
• Binding Sites
• Cell Line
• Drug Design
• HIV Envelope Protein gp41 (antagonists & inhibitors, chemistry, metabolism)
• HIV Fusion Inhibitors (chemistry, pharmacology)
• HIV Infections (drug therapy, virology)
• HIV-1 (drug effects, metabolism)
• Humans
• Models, Molecular
• Molecular Sequence Data