Structure-Based Design of First-Generation Small Molecule Inhibitors Targeting the Catalytic Pockets of AID, APOBEC3A, and APOBEC3B
Justin J. King, Faezeh Borzooee, Junbum Im, Mahdi Asgharpour, Atefeh Ghorbani, Cody P. Diamond, Heather Fifield, Lesley Berghuis, Mani Larijani
Abstract
inhibition of AID and A3A, exhibiting the strongest potency for A3A. Docking suggests key interactions between their warheads and residues lining the catalytic pockets of AID, A3A, and A3B and between the tails and DNA-interacting residues on the surface proximal to the catalytic pocket opening. Accordingly, mutants of these residues decreased inhibition potency. The chemistry and abundance of key stabilizing interactions between the small molecules and residues within and immediately outside the catalytic pockets are promising for therapeutic development.
Topics & Concepts
Cytidine deaminaseSmall moleculeActivation-induced (cytidine) deaminaseChemistryOxidoreductaseEnzymeMutantBiochemistryBiologyAntibodySomatic hypermutationGeneticsGeneB cellChronic Lymphocytic Leukemia ResearchMonoclonal and Polyclonal Antibodies ResearchCAR-T cell therapy research