Potent inhibitors active against HIV reverse transcriptase with K101P, a mutation conferring rilpivirine resistance

Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.Fil: Gray, William T.. University of Yale; Estados UnidosFil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Laskey, Sarah B.. University Johns Hopkins; Estados UnidosFil: Mislak, Andrea C.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Lee, Won Gil. University of Yale; Estados UnidosFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Yale; Estados UnidosFil: Siliciano, Robert F.. University Johns Hopkins; Estados Unidos. Howard Hughes Medial Institute; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

Insights into the Molecular Mechanism of Polymerization and Nucleoside Reverse Transcriptase Inhibitor Incorporation by Human PrimPol

axonometric projectio

A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase

Background Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are vital in treating HIV-1 infection by inhibiting reverse transcriptase (RT). Drug toxicity and resistance drive the need for effective new inhibitors with improved physiochemical properties and potent antiviral activity. Computer-aided and structure-based drug design have guided the addition of solubilizing substituents to the diaryltriazine scaffold. These derivatives have markedly improved solubility and maintain low nanomolar antiviral activity against RT. The molecular and structural basis of inhibition for this series was determined to facilitate future inhibitor development with improved pharmacological profiles. Methods The molecular mechanism of inhibition was investigated using transient-state kinetic analysis. Crystal structures of RT in complex with each inhibitor were obtained to investigate the structural basis of inhibition. Results The diaryltriazine and its morpholine derivative have RT inhibition constants of 9 ± 2 nM and 14 ± 4 nM, respectively. They adopt differential binding modes within the non-nucleoside inhibitor binding pocket to distort the catalytic site geometry and primer grip regions. The novel morpholinopropoxy substituent extends into the RT/solvent interface of the NNIBP. Conclusions Kinetic and structural analyses show that these inhibitors behave as conventional NNRTIs and inhibit the polymerization step. This study confirms that appending solubilizing substituents on the azine ring of diaryltriazine class of NNRTIs that extend into the RT/solvent interface effectively maintains low nanomolar potency and improves physiochemical properties. General significance The modification of NNRTI scaffolds with solubilizing substituents, which extend into the RT/solvent interface, yields potent antivirals and is an effective strategy for developing novel inhibitors with improved pharmacological properties.Fil: Mislak, Andrea C.. University of Yale; Estados UnidosFil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

Crystal Structures of HIV‑1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design

X-ray crystal structures at 2.9 Å resolution are reported for two complexes of catechol diethers with HIV-1 reverse transcriptase. The results help elucidate the structural origins of the extreme antiviral activity of the compounds. The possibility of halogen bonding between the inhibitors and Pro95 is addressed. Structural analysis reveals key interactions with conserved residues P95 and W229 of importance for design of inhibitors with high potency and favorable resistance profiles