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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 1E7-03 compound binds to the PP1 RVxF-accommodating site. Iterative chemical alterations to 1E7-03 furnished a new analogue, HU-1a , with enhanced HIV-1 inhibitory activity and improved metabolic stability compared to 1E7-03 . In a Split NanoBit competition assay, HU-1a primarily bound to the PP1 RVxF-accommodating site. In conclusion, our study identified HU-1a 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.