Almost all discussions of prebiotic chemistry assume that amino acids, nucleotides, and possibly other monomers were first formed on the Earth or brought to it in comets and meteorites, and then condensed nonenzymatically to form oligomeric products. However, attempts to demonstrate plausibly prebiotic polymerization reactions have met with limited success. We show that carbonyl sulfide (COS), a simple volcanic gas, brings about the formation of peptides from amino acids under mild conditions in aqueous solution. Depending on the reaction conditions and additives used, exposure of α-amino acids to COS generates peptides in yields of up to 80% in minutes to hours at room temperature.

Adaptable DNA Analogs: The defining feature of DNA as a genetic blueprint is its capacity for self-replication. In the cell, however, the replication process requires the assistance of multiple elaborate enzymes. How then at the origin of life could DNA or its precursor replicate before enzymes were present? Ura et al. (p. 73 , published online 11 June) have achieved the long-sought goal of preparing a synthetic DNA analog that can dynamically adapt its sequence in free solution. Their analog (as yet only studied in relatively short, 20-unit oligomers) replaces DNA's sugar and phosphate backbone by a peptide strand in which cysteines reversibly bind the conventional DNA bases through thioester tethers. These strands can pair with complementary sequences of true DNA and furthermore swap one tethered base for another if different DNA templating strands are added to the solution in succession.

Significance: One of the long-standing questions in origins-of-life research centers on how the proteinaceous side chains and the protein backbone were selected during the earliest phases of evolution. Here we have studied oligomerization reactions of a group of positively charged amino acids, both proteinaceous and nonproteinaceous. Amino acids spontaneously oligomerized without the use of enzymes or activating agents, under mild, hydroxy acid-catalyzed, dry-down conditions. We observed that the proteinaceous amino acids oligomerized more extensively and with greater preference for reactivity through their α-amine compared with nonproteinaceous amino acids, forming predominantly linear, protein-like backbone topologies. These findings provide a purely chemical basis for selection of the positively charged amino acids found in today’s proteins.

The close synergy between peptides and nucleic acids in current biology is suggestive of a functional co-evolution between the two polymers. Here we show that cationic proto-peptides (depsipeptides and polyesters), either produced as mixtures from plausibly prebiotic dry-down reactions or synthetically prepared in pure form, can engage in direct interactions with RNA resulting in mutual stabilization. Cationic proto-peptides significantly increase the thermal stability of folded RNA structures. In turn, RNA increases the lifetime of a depsipeptide by >30-fold. Proto-peptides containing the proteinaceous amino acids Lys, Arg, or His adjacent to backbone ester bonds generally promote RNA duplex thermal stability to a greater magnitude than do analogous sequences containing non-proteinaceous residues. Our findings support a model in which tightly-intertwined biological dependencies of RNA and protein reflect a long co-evolutionary history that began with rudimentary, mutually-stabilizing interactions at early stages of polypeptide and nucleic acid co-existence.

The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic d,l-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state. Daily oral administration of the peptides in WD-fed LDLr^−/− mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.