CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Poster Abstracts

Conclusions: Adherence to the single daily tablet of LDV/SOF in this urban population was high and coupled with complete HCV viral suppression. However, adherence significantly declined over the course of treatment, suggesting that shorter duration DAA therapies should be evaluated for HCV treatment efficacy in this patient population.

693 Investigation of the Role of Macrocyclization in HCV Protease Inhibitor MK-5172 Djadé I. Soumana ; Kristina Prachanronarong; Nese KurtYilmaz; Ali Akbar; Cihan Aydin; Celia A. Schiffer University of Massachusetts Medical School, Worcester, MA, US

Background: Structure guided drug design has been a powerful tool for the discovery and development of inhibitors to the viral HCV NS3/4A protease. The NS3/4A protease inhibitors (PIs) have benefited from extensive optimizations in the common P4 capping, P3-P1’ peptidomimetic scaffold and various macrocyclization states. However, neither structural nor thermodynamic information have been presented evaluating the benefits of different protease macrocyclization states in the context of resistance. MK-5172 is extremely potent against the wildtype (WT) enzyme, while subverting resistance to R155K and D168A due to packing against the protease catalytic triad, this inhibitor is susceptible to A156T due to a strong steric clash Methods: A combination of standard protein crystallographic, molecular dynamic, kinetic and thermodynamics methods were applied to the protease domain of HCV NS3/4A WT and A156T resistance variant. Detailed structural analysis, including fit within the substrate envelope and dynamic inhibitor envelope, was applied to a series of MK-5172 macrocyclic analogs and compared to the parent MK5172. This data was compared with the thermodynamics of inhibitor binding. Results: A crystallographic, biochemical and thermodynamic characterization of the role of macrocyclization in drug resistance will be presented for the HCV NS3/4A PI MK-5172 and a series of analogs. Through a series of crystal structures in complex with WT and A156T HCV protease variants compared with thermodynamic data we provide atomic level insight into the inhibitor’s unique binding mode and how the macrocyclization impacts susceptibility to drug resistance

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CROI 2015