Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design.

Melanocortin 4 receptor (MC4-R) antagonists are actively sought for treating cancer cachexia. We determined the structures of complexes with and . These peptides differ from by substituting His with Pro and inserting Gly or Arg.

Structure-Based Design and Synthesis of Stapled Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases.

Following a rational design, a series of macrocyclic ("stapled") peptidomimetics of Panx1, the most established peptide inhibitor of Pannexin1 (Panx1) channels, were developed and synthesized. Two macrocyclic analogues and outperformed the linear native peptide. During adenosine triphosphate (ATP) release and Yo-Pro-1 uptake assays in a Panx1-expressing tumor cell line, both compounds were revealed to be promising bidirectional inhibitors of Panx1 channel function, able to induce a two-fold inhibition, as compared to the native Panx1 sequence.

Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide Panx1.

Pannexin1 channels facilitate paracrine communication and are involved in a broad spectrum of diseases. Attempts to find appropriate pannexin1 channel inhibitors that showcase target-selective properties and in vivo applicability remain nonetheless scarce. However, a promising lead candidate, the ten amino acid long peptide mimetic Panx1 (H-Trp-Arg-Gln-Ala-Ala-Phe-Val-Asp-Ser-Tyr-OH), has shown potential as a pannexin1 channel inhibitor in both in vitro and in vivo studies.

Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels.

Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections.

Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure†.

The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist (Ac-Nle-c[Asp-His-DNal(2')-Arg-Trp-Lys]-NH).

Controlling Dipole Orientation through Curvature: Aromatic Foldamer Bent β-Sheets and Helix-Sheet-Helix Architectures.

The helix, turn, and β-strand motifs of biopolymer folded structures have been found to prevail also in non-natural backbones. In contrast, foldamers with aryl rings in their main chains possess distinct conformations that may give access to folded objects beyond the reach of peptidic and nucleotidic backbones. In search of such original architectures, we have explored the effect of bending aromatic amide β-sheets using building blocks that impart curvature.