Applications of Surface Plasmon Resonance SPR in HIV-1 Nef Inhibitor Discovery & PROTAC Development

A Reichert 4SPR was used to help researchers study the interaction between HIV-1 Nef and various inhibitors.  Previous work using small molecules for inhibitors showed some limitations when it came to drug development so PROTAC development was initiated.  Researchers found multiple PROTACS that bound to HIV-1 Nef variants.

Abstract
The HIV-1 Nef accessory factor promotes viral replication and immune escape of HIV-infected cells, making it an attractive drug target. Previously identified small molecules that bind directly to Nef and suppress HIV-1 replication in vitro also reverse Nef-mediated MHC-I downregulation in latently infected CD4+ T cells. These interactions involve multiple Nef surfaces, complicating medicinal chemistry optimization of drug candidates. To address this issue, PROTAC development was initiated for the targeted degradation of Nef. Researchers identified 12 PROTAC analogs that significantly enhanced Nef ubiquitylation. Six of these analogs restored cell surface CD4 and MHC-I expression in T cells by more than 50% while inducing a proportional reduction in Nef levels. Using SPR, researchers demonstrated direct binding of the active analogs to eight HIV-1 Nef variants with KD values in the nM to low µM range, supporting broad spectrum activity against HIV-1. Results from SPR and other techniques support the hypothesis that PROTAC-mediated Nef degradation can reverse all Nef functions.
 
Speaker Biography:
Thomas E. Smithgall, Ph.D., is the William S. McEllroy Professor of Biochemistry in the Department of Microbiology and Molecular Genetics at the University of Pittsburgh School of Medicine. Dr. Smithgall earned his Ph.D. in Pharmacology from the University of Pennsylvania School of Medicine. Following postdoctoral training at the National Cancer Institute, NIH, he held faculty positions at Georgetown University and the University of Nebraska Medical Center before joining the faculty of the University of Pittsburgh in 1998. Dr. Smithgall’s current research interests center on protein-tyrosine kinase signaling and drug discovery related to HIV/AIDS and myeloid leukemias. He has authored or co-authored more than 160 peer-reviewed publications to date and has been continuously supported by NIH grants since 1993. He is inventor or co-inventor on six patents related to HIV-1 Nef inhibitor development as a new approach to AIDS therapy.

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