HIV gp41 C-terminal heptad repeat contains multifunctional domains. Relation to mechanisms of action of anti-HIV peptides.
T20 (Fuzeon), a novel anti-human immunodeficiency virus (HIV) drug, is a peptide derived from HIV-1 gp41 C-terminal heptad repeat (CHR). Its mechanism of action has not yet been defined. We applied Pepscan strategy to determine the relationship between functional domains and mechanisms of action of five 36-mer overlapping peptides with a shift of five amino acids (aa): CHR-1 (aa 623-658), C36 (aa 628-663), CHR-3 (aa 633-668), T20 (aa 638-673), and CHR-5 (aa 643-678). C36 is a peptide with addition of two aa to the N terminus of C34. Peptides CHR-1 and C36 contain N-terminal heptad repeat (NHR)- and pocket-binding domains. They inhibited HIV-1 fusion by interacting with gp41 NHR, forming stable six-helix bundles and blocking gp41 core formation. Peptide T20 containing partial NHR- and lipid-binding domains, but lacking pocket-binding domain, blocked viral fusion by binding its N- and C-terminal sequences with gp41 NHR and cell membrane, respectively. Peptide CHR-3, which is located in the middle between C36 and T20, overlaps >86% of the sequences of these two peptides, and lacks pocket- and lipid-binding domains, exhibited marginal anti-HIV-1 activity. These results suggest that T20 and C36 contain different functional domains, through which they inhibit HIV-1 entry with distinct mechanisms of action. The multiple functional domains in gp41 CHR and their binding partners may serve as targets for rational design of new anti-HIV-1 drugs and vaccines.
Liu
Shuwen
S
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: liusw269@gmail.com.
Jing
Weiguo
W
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021.
Cheung
Byron
B
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021.
Lu
Hong
H
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021.
Sun
Jane
J
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021.
Yan
Xuxia
X
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021.
Niu
Jinkui
J
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021.
Farmar
James
J
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021.
Wu
Shuguang
S
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Jiang
Shibo
S
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021. Electronic address: sjiang@nybloodcenter.org.
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects / Q000235:genetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis; D020449:Repetitive Sequences, Amino Acid
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins