Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound (D) PPA-1 could bind PD-L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that (D) PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.

Intramolecular ligation of peptide hydrazides is reported to occur readily, causing the lactamization of fully unprotected peptides in an epimerization-free manner. This method relies on the routine procedures of Fmoc solid-phase peptide synthesis. It can be used to prepare cyclic peptides and cyclic proteins under simpler, mild conditions at lower costs.

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An operationally simple method for the synthesis of peptide thioesters is developed using standard Fmoc solid-phase peptide synthesis procedures. The method relies on the use of a premade enamide-containing amino acid which, in the final TFA cleavage step, renders the desired thioester functionality through an irreversible intramolecular N-to-S acyl transfer.

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Cyclotides constitute a fascinating family of circular proteins containing ca. 30 amino acid residues. They have a unique cyclic cysteine knot topology and exhibit remarkable thermal, chemical and enzymatic stabilities. These characteristics enable them to have a range of biological activities and promising pharmaceutical and agricultural applications. Here, we present a practical strategy for the chemical synthesis of cyclotides through the intramolecular ligation of fully unprotected peptide O-esters. This strategy involves the mild Fmoc solid-phase peptide synthesis of the peptide O-ester backbone, the head-to-tail cyclization of the cyclotide backbone by native chemical ligation, and the oxidative refolding to yield the natural knot protein. The simplicity and high efficiency of the strategy can be employed in the synthesis of artificial cyclotides for pharmaceutical applications. cyclotides, chemical synthesis, peptide O-ester, native chemical ligation, macrolactamization

Das antimikrobielle Peptid Tachyplesin I wurde als Modell für die Titelstrategie verwendet, die zur Herstellung von peptidischen Makrocyclen mit doppeltem Disulfidersatz entwickelt wurde. Die Faltung und Aktivität der Analogen von Tachyplesin I variierten abhängig von den Disulfidsurrogaten. SPPS=Festphasenpeptidsynthese.

Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as ap romising immunotherapyf or treating cancers.U sing the technology of mirror-image phage display,wedeveloped the first hydrolysisresistant d-peptide antagonists to target the PD-1/PD-L1 pathway.T he optimizedc ompound D PPA-1 could bind PD-L1 at an affinity of 0.51 mm in vitro.Ablockade assaya tt he cellular level and tumor-bearing mice experiments indicated that D PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo.T hus d-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.Scheme 1. A) The PD-1/PD-L1 interaction mediates cancer immune escape. B) d-Peptide antagonists targeting PD-L1 can inhibit the PD-1/ PD-L1 interaction for cancer immunotherapy.