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Drug Discovery

Chemists synthesize and screen massive library of nonnatural proteins

Such screens could yield protein drugs with advantages over natural ones

by Stu Borman
May 24, 2018 | A version of this story appeared in Volume 96, Issue 22


Model of EETI-II, the native protein upon which the xenoprotein libraries are based.
Credit: Proc. Natl. Acad. Sci. USA
Chemists varied a nine-amino-acid string (green) in EETI-II. The protein's β-sheets are shown as flat, gray areas, and its disulfide bonds are indicated in yellow.

Researchers have synthesized and screened a library of small proteins composed entirely of nonnatural amino acids. In these 29-amino-acid miniproteins, called xenoproteins because of their “foreign” content, all the natural l-amino acids were replaced with mirror-image d-amino acids.

Such libraries could yield novel therapeutic agents with key advantages over natural protein-based drugs. Nonnatural miniproteins have enhanced temperature stability, making it easier to store and transport them without refrigeration, and the biomolecules resist enzymatic breakdown in the body.

Bradley L. Pentelute and coworkers at Massachusetts Institute of Technology used combinatorial solid-phase synthesis to create a library of 200 million xenoproteins based on EETI-II, a 29-residue protein with three disulfide links that fold it into a knot. In a string of nine residues in a protein loop, the team varied the amino acids randomly from a group of 16 d-amino acids (Proc. Natl. Acad. Sci. USA 2018, DOI: 10.1073/pnas.1722633115).

Most previous nonnatural peptide libraries had fewer members, consisted of smaller molecules, and varied fewer positions, the researchers say. Pentelute and coworkers evaluated one-tenth of the massive library and isolated specific xenoproteins that bound to an antibody by using both magnetic and fluorescent screening methods. They then used a combination of liquid chromatography and tandem mass spectrometry to identify sequences of the most potent binders.

The group is currently collaborating with the U.S. Army Medical Research Institute of Infectious Diseases to use a xenoprotein library to identify modified miniproteins that bind an Ebola virus glycoprotein.


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