Enhancing the pharmaceutical properties of protein drugs by ancestral sequence reconstruction.

Philip M ZakasHarrison C BrownKristopher KnightShannon L MeeksH Trent SpencerEric A GaucherChristopher B Doering

Published in: Nature biotechnology (2016)

Optimization of a protein's pharmaceutical properties is usually carried out by rational design and/or directed evolution. Here we test an alternative approach based on ancestral sequence reconstruction. Using available genomic sequence data on coagulation factor VIII and predictive models of molecular evolution, we engineer protein variants with improved activity, stability, and biosynthesis potential and reduced inhibition by anti-drug antibodies. In principle, this approach can be applied to any protein drug based on a conserved gene sequence.

Keyphrases

amino acid
protein protein
copy number
small molecule
gene expression
drug induced
adverse drug
data analysis