Structural Optimization of 2,3-Dihydro-1H-cyclopenta[]quinolines Targeting the Noncatalytic RVxF Site of Protein Phosphatase 1 for HIV-1 Inhibition.

Combination antiretroviral therapy (cART) suppresses human immunodeficiency virus-1 (HIV-1) replication but is unable to permanently eradicate HIV-1. Importantly, cART does not target HIV-1 transcription, which is reactivated in latently infected reservoirs, leading to HIV-1 pathogenesis including non-infectious lung, cardiovascular, kidney, and neurodegenerative diseases. To address the limitations of cART and to prevent HIV-1-related pathogenesis, we developed small molecules to target the noncatalytic RVxF-accommodating site of protein phosphatase-1 (PP1) to prevent HIV-1 transcription activation. The PP1 RVxF-accommodating site is critical for the recruitment of regulatory and substrate proteins to PP1. Here, we confirm that our previously developed compound binds to the PP1 RVxF-accommodating site. Iterative chemical alterations to furnished a new analogue, , with enhanced HIV-1 inhibitory activity and improved metabolic stability compared to . In a Split NanoBit competition assay, primarily bound to the PP1 RVxF-accommodating site. In conclusion, our study identified as a promising HIV-1 transcription inhibitor and showed that the PP1 RVxF-accommodating site is a potential drug target for the development of novel HIV-1 transcription inhibitors.