Enhancing the pharmaceutical properties of protein drugs by ancestral sequence reconstruction

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 m...

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Bibliographic Details
Published in:Nature biotechnology 2017-01, Vol.35 (1), p.35-37
Main Authors: Zakas, Philip M, Brown, Harrison C, Knight, Kristopher, Meeks, Shannon L, Spencer, H Trent, Gaucher, Eric A, Doering, Christopher B
Format: Article
Language:English
Subjects:
Amino acid sequencing
Bioengineering
Biological products
Biosynthesis
Conserved Sequence - genetics
Drug Discovery - methods
Drug interactions
Drug Synergism
Evolution
Factor VIII - genetics
Factor VIII - therapeutic use
Hominids
Methods
Observations
Pharmaceuticals
Protein Engineering - methods
Proteins
Proteins - genetics
Proteins - therapeutic use
Sequence Homology, Amino Acid
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Summary: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.
ISSN:1087-0156
1546-1696
DOI:10.1038/nbt.3677