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AIDS. 2014 Jun 1;28(9):1251-60. doi: 10.1097/QAD.0000000000000255.

Hydrophobic mutations in buried polar residues enhance HIV-1 gp41 N-terminal heptad repeat-C-terminal heptad repeat interactions and C-peptides' anti-HIV activity.

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aMOE Key Laboratory of Structure-Based Drug Design & Discovery, Shenyang Pharmaceutical University, Shenyang bDepartment of Medicinal Chemistry, Beijing Institute of Pharmacology & Toxicology, Beijing cKey Laboratory of Medical Molecular Virology of MOE/MOH, Shanghai Medical College, Fudan University, Shanghai, China dLindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA. *Lifeng Cai, Keliang Liu and Shibo Jiang contributed equally to this work.



To investigate the effect of mutations in a highly conserved buried polar area on the function of HIV-1 gp41.


During HIV-1 entry, a six helical bundle (6-HB) formation between the C-terminal and N-terminal heptad repeat (CHR and NHR) of gp41 provides energy for virus cell membrane fusion. In 6-HB, residues at a and d (a-d) positions of CHR directly interact with NHR and are buried. They are considered critical residues for 6-HB stability and for anti-HIV-1 activity of CHR-derived peptides (C-peptides). Most of a-d residues in CHR are hydrophobic, as buried hydrophobic residues facilitate protein stability. However, HIV-1 gp41 CHR contains a highly conserved polar area with four successive buried a-d polar residues: S649/Q652/N656/E659. We mutated these buried polar residues to hydrophobic residues, either Leu or Ile, and studied its effect on the gp41 NHR-CHR interactions and anti-HIV activities of the C-peptides.


We measured the C-peptide mutants' ability to form 6-HB with NHR, thermal stability of the 6-HBs and C-peptides' inhibitory activity against both T20-sensitive and resistant HIV-1 strains.


All the mutated C-peptides retained their ability to form stable 6-HB with NHR and strongly inhibited HIV-1 replication. Strikingly, S649L and E659I mutations endow C-peptide with a significantly enhanced activity against T20-resistant HIV-1 strains.


The highly conserved buried a-d polar residues in HIV-1 gp41 CHR can be mutated as a means of developing new fusion inhibitors against drug-resistant HIV-1 strains. The concept can also be utilized to design fusion inhibitors against other viruses with similar mechanisms.

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