A peptide triple agonist of GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors promotes glycemic control and weight loss.

Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). We demonstrate that two peptide biased agonists (GEP44 and GEP12) of the GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors (GLP-1R, Y1-R, and Y2-R, respectively) elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of insulin secretion in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. These agonists also promote insulin-independent Y1-R-mediated glucose uptake in muscle tissue ex vivo and more profound reductions in food intake and body weight than liraglutide when administered to diet-induced obese rats. Our findings support a role for Y1-R signaling in glucoregulation and highlight the therapeutic potential of simultaneous receptor targeting to achieve long-term benefits for millions of patients.

Harnessing Multiple, Nonproteogenic Substitutions to Optimize CSP:ComD Hydrophobic Interactions in Group†1 Streptococcus pneumoniae.

Streptococcus pneumoniae (pneumococcus) is a human pathobiont that causes drastic antibiotic-resistant infections and is responsible for millions of deaths universally. Pneumococcus pathogenicity relies on the competence-stimulating peptide (CSP)-mediated quorum-sensing (QS) pathway that controls competence development for genetic transformation and, consequently, the spread of antibiotic resistance and virulence genes. Modulation of QS in S. pneumoniae can therefore be used to enervate pneumococcal infectivity as well as minimize the susceptibility to resistance development. In this work, we sought to optimize the interaction of CSP1 with its cognate transmembrane histidine kinase receptor (ComD1) through substitution of proteogenic and nonproteogenic amino acids on the hydrophobic binding face of CSP1. The findings from this study not only provided additional structure-activity data that are significant in optimizing CSP1 potency, but also led to the development of potent QS modulators. These CSP-based QS modulators could be used as privileged scaffolds for the development of antimicrobial agents against pneumococcal infections.