Discovery of Potent HIV-1 Capsid Assembly Inhibitors

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Capsid Assembly Assay (CAA) + Presence of inhibitor B B B Streptavidin Capsid assembly assay is sensitive to: - Mutations in both NTD and CTD of CA - Activity of CAP inhibitors Boehringer Ingelheim - CROI 2010 4
High Throughput Screening (HTS) and hit analysis Several chemically distinct clusters of selective hits (chemotypes) were obtained – 2 chemotypes were chosen for Lead Optimization based on multiple parameters including: – NMR and co-crystallography inhibitors bound to CA-NTD BI 257 BI 060 O H N F F F N N O O N N OH O N N O N N F HO O N EC 50 : Benzodiazepines (BD) 70 ± 30nM (n=21) Benzimidazoles (BIM) – Resistance selection & Mode-of-Action (MoA) studies were performed – MoA was consistent with inhibition of capsid assembly Boehringer Ingelheim - CROI 2010 5 F 62 ± 23 nM (n=53) CC 50 : >28μM ≥20μM F
Page 1 and 2: Discovery of Potent HIV-1 Capsid As
Page 3: Capsid Assembly Assay (CAA) In the
Page 7 and 8: Overview of inhibitor binding withi
Page 9 and 10: Summary of resistance mutations •
Page 11 and 12: EM studies reveal MoA of CAIs BD DM
Page 13 and 14: Summary • Identified two chemotyp
Page 15: HIV Capsid - Acknowledgements Boehr

Discovery of Potent HIV-1 Capsid Assembly Inhibitors

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