Lenacapavir, the long-acting HIV capsid inhibitor, is one of the most celebrated drugs of the decade, but its multi-step chemical synthesis is costly and slow, a genuine obstacle to global access. Scientists at the Manchester Institute of Biotechnology have engineered an enzyme that manufactures a key chiral intermediate of the drug biologically, reporting the work in the Journal of the American Chemical Society.
The starting enzyme, an aminotransferase, had no detectable activity on the target substrate at all. Using directed evolution in a substrate walking approach, the team ran eight rounds of engineering and screened more than 12,000 variants, with enzyme panels supplied by the biocatalysis firm Prozomix. Ten accumulated mutations added activity, improved stability and reshaped the active site to accept the bulky ketone precursor, and X-ray crystallography resolved the engineered enzyme's three-dimensional structure.
Under industrially relevant conditions, the biocatalytic route converted 98 per cent of the starting material with a yield above 90 per cent and enantiomeric excess above 99 per cent, delivering the correct chiral amine core in a single enzymatic step. Beyond this one medicine, the study is a demonstration of how far directed evolution can now carry an enzyme from zero activity to manufacturing performance.