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 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.
Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, Georgia, USA.
Philip M
http://orcid.org/0000-0002-4919-5182
PM
Zakas
Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, Georgia, USA.
Harrison C
HC
Brown
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Kristopher
K
Knight
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Shannon L
http://orcid.org/0000-0002-3683-8644
SL
Meeks
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.
H Trent
HT
Spencer
School of Biology, Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia, USA.
Eric A
EA
Gaucher
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.
Christopher B
CB
Doering
D017124:Conserved Sequence / Q000235:genetics*; D055808:Drug Discovery / Q000379:methods*; D004357:Drug Synergism; D005169:Factor VIII / Q000235:genetics* / Q000627:therapeutic use; D015202:Protein Engineering / Q000379:methods*; D011506:Proteins / Q000235:genetics* / Q000627:therapeutic use; D017386:Sequence Homology, Amino Acid
D011506:Proteins; D005169:Factor VIII
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