Method determines plausible forms of ancestral blood clotting protein | Chemical & Engineering News
Volume 94 Issue 39 | p. 13 | Concentrates
Issue Date: October 3, 2016

Method determines plausible forms of ancestral blood clotting protein

Resurrected sequences have better pharmaceutical properties than modern human factor VIII
Department: Science & Technology
News Channels: Biological SCENE
Keywords: biologics, ancestral sequence reconstruction, factor VIII, proteins, gene therapy
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Ancestral sequence reconstruction predicts how human coagulation factor VIII (gray) differs from its ancestors (colored regions).
Credit: Philip Zakas
Structure of human factor VIII showing the spots at which it differs from ancestors.
 
Ancestral sequence reconstruction predicts how human coagulation factor VIII (gray) differs from its ancestors (colored regions).
Credit: Philip Zakas

Ancestral sequence reconstruction (ASR) is a computational method in which the sequences of closely related proteins from different species are used to infer ancient protein sequences within a predicted evolutionary tree. Christopher B. Doering of Emory University, Eric A. Gaucher of Georgia Tech, and coworkers have used ASR to improve the pharmaceutical properties of coagulation factor VIII, a protein essential to blood clotting (Nat. Biotechnol. 2016, DOI: 10.1038/nbt.3677). Deficiency in factor VIII is the cause of hemophilia A, and infusion of the protein is used to treat the disease. Unfortunately, many people who receive therapeutic factor VIII develop antibodies to it. Plus, recombinant human factor VIII is hard to produce in cell culture manufacturing systems. By using ASR, Doering and coworkers constructed a family tree of factor VIII ancestors from which they selected 14 proteins for evaluation. Several of these ancestral proteins were produced more efficiently, were more potent, were less immune-reactive, and remained active longer than modern human factor VIII. Doering’s group is now working with the ancestral sequences as potential gene therapy agents, as well as extending the general ASR approach to other pharmaceutically relevant blood coagulation factors.

 
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