COVALENT DRUG BINDING: A MECHANISTIC EXPLORATION TO ENHANCE SAFETY AND EFFICACY

Abstract

COVALENT DRUG BINDING TO PROTEINS RESULTS IN DELETERIOUS EFFECTS. ADVERSE DRUG REACTIONS OCCUR WHEN OVERT COVALENT BINDING ALTERS PROTEIN STRUCTURE AND FUNCTION DIRECTLY, OR INDIRECTLY, BY COVERTLY INDUCING ABERRANT PROTEIN POST-TRANSLATIONAL MODIFICATIONS SUCH AS PROTEIN GLUTATHIONYLATION. USING ACETAMINOPHEN (APAP) AS A MODEL TOXICANT, WE UNCOVERED A SUITE OF PROTEINS GLUTATHIONYLATED BY APAP, AND CORRELATED THEM TO SIGNATURES OF APAP HEPATOTOXICITY USING PROTEO-METABONOMIC MAPPING. BASED ON THE MAPPING, WE FURTHER ELUCIDATED THE MECHANISMS OF ACTION OF PROPHYLACTICS AND ANTIDOTES AGAINST APAP HEPATOTOXICITY. OVERT COVALENT BINDING CAN LEAD TO INACTIVATION OF CYP450 ENZYMES AND CAUSE DRUG-DRUG INTERACTIONS (DDIS). WE EXPLORED DRUG DEUTERATION TO REDUCE REACTIVE METABOLITE FORMATION AND PATIENT GENOTYPING TO STRATIFY SUSCEPTIBILITY TO DDIS CAUSED BY LAPATINIB. WE NEGATED THE APPARENT LIABILITY OF COVALENT BINDING BY INVESTIGATING THE INTERACTION BETWEEN LAPATINIB AND ENDOXIFEN, REVEAL