Structure–Activity Relationships of Natural and Semisynthetic Plecomacrolides Suggest Distinct Pathways for HIV‑1 Immune Evasion and Vacuolar ATPase-Dependent Lysosomal Acidification

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. This analysis demonstrated
that the most potent compounds were natural concanamycins and their
derivatives. Comparison against a set of new, semisynthetic concanamycins
revealed that substituents at C-8 and acylation of C-9 significantly
affected Nef potency, target cell viability, and lysosomal neutralization.
These findings provide important progress toward understanding the
mechanism of action of these compounds and the identification of an
advanced lead anti-HIV Nef inhibitory compound.