Enhancing the pharmaceutical properties of protein drugs by ancestral sequence reconstruction

• Type of Material: Article
• Authors: Philip M. Zakas, Emory University; Harrison C. Brown, Emory University; Kristopher Knight, Emory University; Shannon Meeks, Emory University; Harold Spencer, Emory University; Eric A. Gaucher, Georgia Institute of Technology; Christopher Doering, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nbt.3677
• Title of Journal or Parent Work: Nature Biotechnology
• ISSN: 1087-0156
• Volume: 35
• Issue: 1
• Start Page: 35
• End Page: 37
• Keywords: Life Sciences & Biomedicine; IDENTIFICATION; HIGH-LEVEL EXPRESSION; Science & Technology; DOMAIN; A2 SUBUNIT DISSOCIATION; COAGULATION-FACTOR-VIII; EVOLUTIONARY HISTORY; Biotechnology & Applied Microbiology
• Research Categories: Engineering, Biomedical; Health Sciences, Pharmacology

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.