Non-peptide entry inhibitors of HIV-1 that target the gp41 coiled coil pocket.
The ectodomain of HIV-1 gp41 mediates the fusion of viral and host cellular membranes. The peptide-based drug Enfuvirtide(1) is precedent that antagonists of this fusion activity may act as anti HIV-agents. Here, NMR screening was used to discover non-peptide leads against this target and resulted in the discovery of a new benzamide 1 series. This series is non-peptide, low molecular weight, and analogs have activity in a cell fusion assay with EC50 values ranging 3-41microM. Structural work on the gp41/benzamide 1 complex was determined by NMR spectroscopy using a designed model peptide system that mimics an open pocket of the fusogenic form of the protein.
Stewart
Kent D
KD
Pharmaceutical Discovery Division, Abbott Laboratories, 100 Abbott Park Rd., R46Y, AP10, Abbott Park, IL 60064-6098, United States. kent.d.stewart@abbott.com
Huth
Jeffrey R
JR
Ng
Teresa I
TI
McDaniel
Keith
K
Hutchinson
Rebecca Newlin
RN
Stoll
Vincent S
VS
Mendoza
Renaldo R
RR
Matayoshi
Edmund D
ED
Carrick
Robert
R
Mo
Hongmei
H
Severin
Jean
J
Walter
Karl
K
Richardson
Paul L
PL
Barrett
Leo W
LW
Meadows
Robert
R
Anderson
Steve
S
Kohlbrenner
William
W
Maring
Clarence
C
Kempf
Dale J
DJ
Molla
Akhter
A
Olejniczak
Edward T
ET
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D001549:Benzamides; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide; C037689:benzamide