Massively parallel de novo protein design for targeted therapeutics.

Nature 2017 10 27;550(7674):74-79. Epub 2017 Sep 27.

Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.

De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature23912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802399PMC
October 2017
180 Reads

Publication Analysis

Top Keywords

novo protein
8
massively parallel
8
protein design
8
influenza haemagglutinin
4
residues target
4
target influenza
4
antibodies lose
4
mini-proteins 37-43
4
37-43 residues
4
stable antibodies
4
botulinum neurotoxin
4
6286 control
4
designs extremely
4
extremely stable
4
neurotoxin 6286
4
lose activity
4
haemagglutinin botulinum
4
tested 22660
4
yeast display
4
high temperatures
4

Similar Publications