Gallic acid is a pore-directed ligand of the HIV-1 capsid hexamer with a binding profile distinct from PF74 Restricted; Files & ToC

Abstract

As a crucial global health challenge as well as a biological topic, the study of HIV-1 highly demands the discovery of new drugs or potential new drugs. This study systematically investigates the biochemical mechanism between gallic acid (GA) and the assembled HIV-1 capsid hexamer. Based on thermal shift analysis (TSA), GA produced a stable and reproducible positive thermal shift on the CA121 hexamer model, indicating that it is not a non-specific stabilizer of the CA but rather tends to recognize the conformation of the assembled hexamer. At the same time, the thermal profile of GA is highly sensitive to the solvent system, pH, and ionic state. Bio-layer interference (BLI) furthermore confirmed that GA binds directly to the assembled CA hexamer in a dose-dependent manner, although its binding affinity is weaker than that of PF74 and IP6. Based on single-point mutation inference, GA binding is most sensitive to the key central pore residue Arg18, together with Lys25. This implies a pore-centered binding mode distinct from the PF74 site-1 pocket. Finally, a comparison of GA derivatives and analogs indicates that GA binding also depends on anionic characteristics, an aromatic skeleton rich in oxygen-containing substituents, and its spatial feature. In conclusion, this study defines GA as a direct, pore-directed, Arg18-directed ligand for the HIV-1 capsid hexamer, revealing its potency as a starting chemical for anti-HIV drug development in the future.

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biophysics, General Biology, Molecular Biology, Virology
Keyword	Capsid hexamer HIV-1 capsid Bio-layer interferometry Pore-directed ligand Thermal shift assay Gallic acid
Committee Chair / Thesis Advisor	Sarafianos, Stefan, Emory University
Committee Members	Cole, Megan, Emory University Veneziani, Alessandro, Emory University

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