Therapeutic efficacy of stable analogues of vasoactive intestinal peptide against pathogens.

Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide recently identified as a potential antimicrobial peptide. To overcome the metabolic limitations of VIP, we modified the native peptide sequence and generated two stable synthetic analogues (VIP51 and VIP51(6-30)) with better antimicrobial profiles. Herein we investigate the effects of both VIP analogues on cell viability, membrane integrity, and ultrastructure of various bacterial strains and Leishmania species.

Protective role of the neuropeptide urocortin II against experimental sepsis and leishmaniasis by direct killing of pathogens.

We currently face an alarming resurgence in infectious diseases characterized by antimicrobial resistance and therapeutic failure. This has generated the urgent need of developing new therapeutic approaches that include agents with nontraditional modes of action. A recent interest focused on approaches based on our natural immune defenses, especially on peptides that combine innate antimicrobial activity against diverse pathogens and immunoregulatory functions.

Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development.

Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase.

Antibacterial agent discovery using thymidylate synthase biolibrary screening.

Thymidylate synthase (TS, ThyA) catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate to 2'-deoxythymidine 5'-monophosphate, an essential precursor for DNA synthesis. A specific inhibition of this enzyme induces bacterial cell death. As a second round lead optimization design, new 1,2-naphthalein derivatives have been synthesized and tested against a TS-based biolibrary, including human thymidylate synthase (hTS).