Design and Synthesis of Nef:SFK Interaction Inhibitors for Application in an Immune-directed HIV-1 Cure
Abstract
The human immunodeficiency virus type 1 (HIV-1) protein, Nef, binds and activates Src family kinases (SFKs) to reduce cell surface levels of major histocompatibility complex class I (MHC-I), thereby facilitating cytotoxic T lymphocyte (CTL) evasion. Importantly, Nef-mediated CTL evasion compromises the success of immune-directed curative approaches, underscoring Nef:SFK interaction inhibitors as promising adjuvants in an immune-directed cure. Previously, our group identified a dipeptide derivative (H3-1) which inhibits the Nef:SFK interaction and MHC-I downregulation in vitro, but is unstable in vivo. I hypothesized that H3-1’s instability is due to its proteolysis and have generated peptidomimetic analogues of H3-1 which are predicted to maintain improved proteolytic stabilities. Herein, I describe the design and synthesis of analogues incorporating carboxyl (methyl ester, amide, nitrile, and tetrazole) and amide (thioamide and methyleneamino) replacing groups. With future biological studies, we aim to identify an in vivo stable Nef:SFK inhibitor for application in an immune-directed HIV-1 cure.