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Nat Biotechnol. 2017 Jan;35(1):35-37. doi: 10.1038/nbt.3677. Epub 2016 Sep 26.

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

Author information

Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, Georgia, USA.
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
School of Biology, Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia, USA.


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.

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Conflict of interest statement

STATEMENT Drs. Doering, Gaucher, Spencer and Zakas are inventors on a patent application describing ancestral FVIII technology filed by Emory University/Children’s Healthcare of Atlanta and Georgia Institute of Technology. Drs. Doering and Spencer are co-founders Expression Therapeutics and own equity in the company. Expression Therapeutics owns the intellectual property associated with ET3. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.

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