Morgan McCauley, Matthew Huston, Alanna R Condren, Filipa Pereira, Joel Cline, Marianne Yaple-Maresh, Mark M Painter, Gretchen E Zimmerman, Andrew W Robertson, Nolan Carney, Christopher Goodall, Valeri Terry, Rolf Müller, David H Sherman, Kathleen L Collins
The human immunodeficiency virus (HIV)-encoded accessory protein Nef enhances pathogenicity by reducing major histocompatibility complex I (MHC-I) cell surface expression, protecting HIV-infected cells from immune recognition. Nef-dependent downmodulation of MHC-I can be reversed by subnanomolar concentrations of concanamycin A ( 1 ), a well-known inhibitor of vacuolar ATPase, at concentrations below those that interfere with lysosomal acidification or degradation. We conducted a structure-activity relationship study that assessed 76 compounds for Nef inhibition, 24 and 72 h viability, and lysosomal neutralization in Nef-expressing primary T cells...
March 7, 2024: Journal of Medicinal Chemistry