All known forms of life use RNA-mediated polypeptide synthesis to produce the proteins encoded in their genes. Because the principal parts of the translational machinery consist of RNA, it is likely that peptide synthesis was achieved early in the prebiotic evolution of an RNA-dominated molecular world. How RNA attracted amino acids and then induced peptide formation in the absence of enzymes has been unclear. Herein, we show that covalent capture of an amino acid as a phosphoramidate favors peptide formation. Peptide coupling is a robust process that occurs with different condensation agents. Kinetics show that covalent capture can accelerate chain growth over oligomerization of the free amino acid by at least one order of magnitude, so that there is no need for enzymatic catalysis for peptide synthesis to begin. Peptide chain growth was also observed on phosphate-terminated RNA strands. Peptide coupling promoted by ribonucleotides or ribonucleotide residues may have been an important transitional form of peptide synthesis that set in when amino acids were first captured by RNA.

Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.

Organisms use enzymes to ensure af lowo f substrates through biosynthetic pathways. How the earliest form of life established biosynthetic networks and prevented hydrolysis of intermediates without enzymes is unclear. Organocatalysts may have played the role of enzymes. Quantitative analysis of reactions of adenosine 5-monophosphate and glycine that produce peptides,p yrophosphates,a nd RNAc hains reveals that organocapture by heterocycles gives hydrolytically stabilized intermediates with balanced reactivity. We determined rate constants for 20 reactions in aqueous solutions containing ac arbodiimide and measured product formation with cyanamide as ac ondensing agent. Organocapture favors reactions that are kinetically slow but productive,a nd networks,o vers ingle transformations.H eterocycles can increase the metabolic efficiency more than two-fold, with up to 0.6 useful bonds per fuel molecule spent, boosting the efficiency of life-like reaction systems in the absence of enzymes.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.

Nucleic acids and polypeptides are at the heart of life. It is interesting to ask whether the monomers of these biopolymers possess intrinsic reactivity that favors oligomerization in the absence of enzymes. We have recently observed that covalently linked peptido RNA chains form when mixtures of monomers react in salt-rich condensation buffer. Here, we report the results of a screen of the 20 proteinogenic amino acids and four ribonucleotides. None of the amino acids prevent phosphodiester formation, so all of them are compatible with genetic encoding through RNA chain growth. A reactivity landscape was found, in which peptide formation strongly depends on the structure of the amino acid, but less on the nucleobase. For example, proline gives ribonucleotide-bound peptides most readily, tyrosine favors pyrophosphate and phosphodiester formation, and histidine gives phosphorimidazolides as dominant products. When proline and aspartic acid were allowed to compete for incorporation, only proline was found at the N-terminus of peptido chains. The reactivity described here links two fundamental classes of biomolecules through reactions that occur without enzymes, but with amino acid specificity.

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Phosphoramidates composed of an amino acid and anucleotide analogue are critical metabolites of prodrugs,such as remdesivir.Hydrolysis of the phosphoramidate liberates the nucleotide,w hichc an then be phosphorylated to become the pharmacologically active triphosphate.E nzymatic hydrolysis has been demonstrated, but as pontaneous chemical process may also occur.W em easured the rate of enzyme-free hydrolysis for 17 phosphoramidates of ribonucleotides with amino acids or related compounds at pH 7.5. Phosphoramidates of proline hydrolyzed fast, with ahalf-life time as short as 2.4 hf or Pro-AMP in ethylimidazole-containing buffer at 37 8 8C; 45-fold faster than Ala-AMP and 120-fold faster than Phe-AMP.C rystal structures of Gly-AMP,P ro-AMP, bPro-AMP and Phe-AMP bound to RNase Aa sc rystallization chaperone showed how well the carboxylate is poised to attack the phosphoramidate,h elping to explain this reactivity.O ur results are significant for the design of new antiviral prodrugs.

Nucleic acids and polypeptides are at the heart of life.I ti si nteresting to ask whether the monomers of these biopolymers possess intrinsic reactivity that favors oligomerization in the absence of enzymes.W eh ave recently observed that covalently linked peptido RNAchains form when mixtures of monomers react in salt-rich condensation buffer.H ere,w e report the results of as creen of the 20 proteinogenic amino acids and four ribonucleotides.N one of the amino acids prevent phosphodiester formation, so all of them are compatible with genetic encoding through RNAc hain growth. A reactivity landscape was found, in whichp eptide formation strongly depends on the structure of the amino acid, but less on the nucleobase.F or example,p roline gives ribonucleotidebound peptides most readily,t yrosine favors pyrophosphate and phosphodiester formation, and histidine gives phosphorimidazolides as dominant products.When proline and aspartic acid were allowed to compete for incorporation, only proline was found at the N-terminus of peptido chains.T he reactivity described here links two fundamental classes of biomolecules through reactions that occur without enzymes,but with amino acid specificity.

A hexapeptide assembled from dipeptide building blocks assumes the secondary structure of the polyproline II (PPII) helix. Side chain-to-backbone hydrogen bonds stabilize peptide torsions next to the fused ring systems. The solution structure of the polyhydroxylated peptide was studied by spectroscopic methods.