Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1
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Ku, Therese, Natalie Lopresti, Matthew Shirley, Mattia Mori, Jan Marchant, Xiao Heng, Maurizio Botta, Michael F. Summers, and Katherine L. Seley-Radtke. “Synthesis of Distal and Proximal Fleximer Base Analogues and Evaluation in the Nucleocapsid Protein of HIV-1.” Bioorganic & Medicinal Chemistry 27, no. 13 (July 1, 2019): 2883–92. https://doi.org/10.1016/j.bmc.2019.05.019.
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Abstract
Anti-HIV-1 drug design has been notably challenging due to the virus’ ability to mutate and develop immunity against commercially available drugs. The aims of this project were to develop a series of fleximer base analogues that not only possess inherent flexibility that can remain active when faced with binding site mutations, but also target a non-canonical, highly conserved target: the nucleocapsid protein of HIV (NC). The compounds were predicted by computational studies not to function via zinc ejection, which would endow them with significant advantages over non-specific and thus toxic zinc-ejectors. The target fleximer bases were synthesized using palladium-catalyzed cross-coupling techniques and subsequently tested against NC and HIV-1. The results of those studies are described herein.