posted on 2021-11-05, 19:11authored byCailen
M. McCloskey, Qingfeng Li, Eric J. Yik, Nicholas Chim, Arlene K. Ngor, Esau Medina, Ivan Grubisic, Lance Co Ting Keh, Ryan Poplin, John C. Chaput
Synthetic genetic
polymers (xeno-nucleic acids, XNAs) have the
potential to transition aptamers from laboratory tools to therapeutic
agents, but additional functionality is needed to compete with antibodies.
Here, we describe the evolution of a biologically stable artificial
genetic system composed of α-l-threofuranosyl nucleic
acid (TNA) that facilitates the production of backbone- and base-modified
aptamers termed “threomers” that function as high quality
protein capture reagents. Threomers were discovered against two prototypical
protein targets implicated in human diseases through a combination
of in vitro selection and next-generation sequencing
using uracil nucleotides that are uniformly equipped with aromatic
side chains commonly found in the paratope of antibody–antigen
crystal structures. Kinetic measurements reveal that the side chain
modifications are critical for generating threomers with slow off-rate
binding kinetics. These findings expand the chemical space of evolvable
non-natural genetic systems to include functional groups that enhance
protein target binding by mimicking the structural properties of traditional
antibodies.