A new strategy based on drug-linker-nanocarrier interactions to design new HIV-1 non-nucleoside reverse transcriptase inhibitors.

The development of effective non-nucleoside inhibitors targeting HIV-1 reverse transcriptase (RT) remains a persistent challenge in AIDS research, particularly in overcoming drug-induced mutations. This study focuses on harnessing the potential of Rilpivirine (RPV), a widely recognized non-nucleoside inhibitor, as a foundational structure for designing and synthesizing inhibitors with superior anti-HIV-1 activities compared to RPV. Through strategic conjugation of RPV to molecular umbrellas using diverse linkers such as BSOCOES, DSP, and EGS, a novel series of potent non-nucleoside inhibitors is crafted. Guided by a structure-based drug design approach, this study unveils a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Comprehensive molecular analyses reveal extensive interactions between these NNRTIs and the RT inhibitor-binding pocket, confirming their superior antiviral efficacy against the wild-type virus when compared to RPVs. The innovative strategy employed in this research, focusing on drug-linker-nanocarrier interactions, introduces a promising avenue for designing and developing robust HIV-1 RT inhibitors with potential clinical applications. The findings emphasize the approach's potential for addressing challenges posed by drug-resistant mutations, opening new possibilities for advancing antiretroviral therapy.