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

ABSTRACT: 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.

SUBMITTER: Zakas PM

PROVIDER: S-EPMC5225049 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Zakas Philip M PM Brown Harrison C HC Knight Kristopher K Meeks Shannon L SL Spencer H Trent HT Gaucher Eric A EA Doering Christopher B CB

Nature biotechnology 20160926 1

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 ...[more]

PMID: 27669166

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