Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.10.30.362111v1?rss=1

Authors: Come, J. A. A. d. S. S., Zhuang, Y., Li, T., Brogi, S., Gemma, S., Liu, T., da Silva, E. R.

Abstract:

Arginase is a metalloenzyme that plays a central role in Leishmania infection. Previously, rosmarinic and caffeic acids were described as antileishmanial and as a Leishmania amazonensis arginase inhibitor and now, we describe the inhibition of arginase in L. amazonensis by rosmarinic acid analogs (1-7) and new caffeic acids derived amides (8-10). Caffeic acid esters and amides were produced by means of the engineered synthesis in E. coli and tested against L. amazonensis arginase. New amides (8-10) were biosynthesized in E. coli cultured with 2 mM of different combinations of feeding substrates. The most potent arginase inhibitors showed Ki(s) between 2 - 5.7 M. Compounds 2-4 and 7 inhibited L-ARG through a noncompetitive mechanism, and 9 showed a competitive inhibition. By applying an in silico protocol we determined the binding mode of compound 9. The competitive inhibitor of L-ARG targets key residues within the binding site of the enzyme establishing a metal coordination bond with the metal ions as well as a series of hydrophobic and polar contacts supporting its micromolar inhibition of L-ARG. These results highlight that the dihydroxycinnamic-derived compounds can be used as the basis for the development of new drugs using a powerful tool based on the biosynthesis of arginase inhibitors.

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