abstract
On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydi-oxy)plieiiyl-2,5-dimethylpyl-role (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A(1), NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that I I compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure-activity relationship and molecular docking analysis revealed that the carboxyl group Could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A(12)), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A(12) could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor.
keywords
IMMUNODEFICIENCY-VIRUS TYPE-1; SUBSTITUTED PYRROLE DERIVATIVES; CORE STRUCTURE; ENTRY INHIBITORS; COILED-COIL; SALT BRIDGE; PEPTIDES; DOMAIN; IDENTIFICATION; GLYCOPROTEIN
subject category
Pharmacology & Pharmacy
authors
Liu, K; Lu, H; Hou, L; Qi, Z; Teixeira, C; Barbault, F; Fan, BT; Liu, SW; Jiang, SB; Xie, L
our authors
Cátia Teixeira
Post-doc FellowshipGroups
acknowledgements
This investigation was supported by grants 2006AA02Z319 and 2006DFA33560 from file Ministry of Science and Technology in China and 2007CY06 from Beijing Municipal Science & Technology Commission to L. Xie, grants 2005Z2-E4041 from Guangzhou Science and Technology Key Project Ind R01 Af46221 frorn the U.S. National Institutes of Health to S. liang, Ind tile Ph.D. fellowship SFRI-I/BD/22 190/ 2005 from Fundaycao para a Ci ncia e a Tecnologia (Portugal) to CAtia Teixeira.