Prebiotic Synthesis of Cysteine Peptides That Catalyze Peptide Ligation in Neutral Water

Peptides and the proteinogenic α-amino acids are essential to all life on Earth. Peptide biosynthesis is orchestrated by a complex suite of enzymes in extant biology, but this must have been predated by a simple chemical synthesis at the origins of life. α-Aminonitriles, the nitrile precursors of α-amino acids, are generally readily produced by Strecker reactions, but the origin of cysteine—the thiol-bearing amino acid—is not understood. The aminothiol moiety of cysteine is chemically incompatible with nitriles at physiological pH, therefore cysteine nitrile is not stable, and it is widely believed that cysteine was a biological invention and a late addition to the genetic code. Here, we report the first high-yielding, prebiotic synthesis of cysteine peptides. Our biomimetic synthesis converts serine to cysteine, by-passing the Strecker reaction of β-mercaptoacetaldehyde, but exploits nitrile–activated dehydroalanine synthesis at near-neutral pH. We additionally demonstrate the catalytic prowess of N-acylcysteines (and related peptides and thiols) in the organocatalytic synthesis of peptides and peptidyl amidines in neutral water. Thiol catalysis directly couples kinetically stable—but energy-rich—α-amidonitriles to proteinogenic amines, in a reaction that tolerates all twenty proteinogenic side chains. This is a rare, prebiotically plausible example of selective and efficient organocatalysis in water. Our results implicate cysteine derivatives and thiol-catalysis at the onset of evolution.