Reaction hijacking compounds as therapeutic modulators
Essential roles in biochemical reactions and well-defined ‘druggable’ pockets make enzymes favoured targets for drug design.
An emerging class of reaction hijacking compounds is reviewed, which exploit the enzyme’s catalytic cycle to generate a potent modulator in situ.
The target enzyme activates and positions the hijacker, catalysing covalent conjugation to a co-substrate or cofactor to generate a tight-binding, chemically stable adduct that inactivates the enzyme.
Susceptible enzymes include members of the superfamily of adenylate-forming enzymes, NAD+ -metabolising enzymes, and enzymes that employ different cofactors.
Reaction hijacking inhibitors hold promise as therapeutics targeting a range of important enzymes, offering good selectivity and potency, synthetic tractability, and druglike properties.
https://www.cell.com/trends/biochemical-sciences/fulltext/S0968-0004(26)00069-1
