Macrocyclization has enabled the use of peptides in drug discovery creating an eed for methods to synthesize diverse peptide macrocycles.A zapeptides have advanced to clinically used drugs,h owever,f ew cyclic azapeptides have been studied. Am ultiple component "A 3 -macrocyclization" strategy is described for the preparation of diverse cyclic azapeptides and is demonstrated by the synthesis of 15 growth hormone releasing hormone-6 (GHRP-6) analogs.C ertain cyclic aza-GHRP-6 analogs exhibited unprecedented affinity for the CD36 receptor,a nd capacity to modulate Toll-like receptor agonist-induced overproduction of nitric oxide,a nd reduce pro-inflammatory cytokine and chemokine production in macrophages.

No abstract

Antimicrobial peptides (AMPs) have attracted great attention as next generation antibiotics for the treatment of multidrug-resistant (MDR) bacterial infections. Poor proteolytic stability has however undermined clinical applications of AMPs. A novel peptide cyclization approach is described to enhance the in vivo antibacterial activity of AMPs. Bicyclic antimicrobial peptides were synthesized by cross-linking the ε-amino groups of three lysine residues with a 1,3,5-trimethylene benzene spacer. In a proof of principal study, four bicyclic peptides were synthesized from the cationic AMP OH-CM6. One bicyclic peptide retained strong antimicrobial activity and low toxicity but exhibited a prolonged half-life in serum. Antibacterial activity was consequently improved in vivo without renal or hepato-toxicity. The novel peptide cyclization approach represents an important tool for enhancing AMP proteolytic stability for improved treatment of bacterial infection.

Cationic antimicrobial peptides (CAMPs) are promising for treatment of multidrug-resistant (MDR) bacteria-caused infections. However, clinical application of CAMPs has been hampered mostly due to their poor proteolytic stability and hemolytic toxicity. Recently, lysine-stapled CAMPs developed by us had been proved to increase peptide stability in vitro without induction of hemolysis. Herein, the applicability of the lysine stapling strategy was further explored by using five natural or artificial CAMPs as model peptides. Lysine stapling screening was implemented to provide 13 cyclic analogues in total. Biological screening of these cyclic analogues showed that CAMPs with a better amphiphilic structure were inclined to exhibit improved antimicrobial activity, protease stability, and biocompatibility after lysine-stapling. One of the stapled analogues of BF15-a1 was found to have extended half-life in plasma, enhanced antimicrobial activity against clinically isolated MDR ESKAPE pathogens, and remained highly effective in combating MRSA infection in a mouse model.