Molecular technologies for pseudo-natural peptide synthesis and discovery of bioactive compounds against undruggable targets

Many protein targets are inherently unsuitable for binding small molecules and have been labeled "undruggable" as a result. New classes of drugs are required for these targets. Peptides can meet this need, provided that they contain certain modifications, e.g. unnatural amino acids and macrocyclic backbone structures. Such peptides are large enough to bind tightly and specifically to protein targets, including those considered undruggable. At the same time, these peptides can be small enough to be membrane permeable, be administered orally, and enter cells. Here, molecular technologies are descried that can be used to find binding peptides for essentially any given protein target. We describe how these technologies can be combined with pseudo-natural peptide synthesis, which allows for the discovery of drug-like peptides that include unnatural amino acids and macrocycles. ©