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Trypanothione disulfide reductase (TryR) is an essential homodimeric enzyme of trypanosomatid parasites that has been validated as a drug target to fight human infections. Using peptides and peptidomimetics, we previously obtained proof of concept that disrupting protein–protein interactions at the dimer interface of Leishmania infantum TryR (LiTryR) offered an innovative and so far unexploited opportunity for the development of novel antileishmanial agents. Now, we show that linking our previous peptide prototype TRL38 to selected hydrophobic moieties provides a novel series of small-molecule–peptide conjugates that behave as good inhibitors of both LiTryR activity and dimerization.

There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure–activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents. After evaluating 63 analogues against human coronavirus 229E, four of the best molecules were selected and shown to have micromolar activity against SARS-CoV-2. Since the action point was situated post virus entry and lying at the stage of viral polyprotein processing and the start of RNA synthesis, enzymatic assays were performed with CoV proteins involved in these processes. While no inhibition was observed for SARS-CoV-2 nsp12-nsp7-nsp8 polymerase, nsp14 N7-methyltransferase and nsp16/nsp10 2’-O-methyltransferase, nor the nsp3 papain-like protease, the compounds clearly inhibited the nsp5 main protease (Mpro). Although the inhibitory activity was quite modest, the plausibility of binding to the catalytic site of Mpro was established by in silico studies. Therefore, the 1,4,4-trisubstituted piperidines appear to represent a novel class of non-covalent CoV Mpro inhibitors that warrants further optimization and development.

N-methylation of the triazole moiety present in our recently described triazole-phenyl-thiazole dimerization disruptors of Leishmania infantum trypanothione disulfide reductase (LiTryR) led to a new class of potent in- hibitors that target different binding sites on this enzyme. Subtle structural changes among representative library members modified their mechanism of action, switching from models of classical competitive inhibition to time- dependent mixed noncompetitive inhibition. X-ray crystallography and molecular modeling results provided a rationale for this distinct behavior. The remarkable potency and selectivity improvements, particularly against intracellular amastigotes, of the LiTryR dimerization disruptors 4c and 4d reveal that they could be exploited as leishmanicidal agents. Of note, L. infantum promastigotes treated with 4c significantly reduced their low- molecular-weight thiol content, thus providing additional evidence that LiTryR is the main target of this novel compound.

[EN] The invention relates to peptides of general formula S, wherein the carboxyl terminus (D-alanine, D-Ala) is replaced by an analogous amino alcohol. The invention also relates to the method for synthesising same and the use of the aforementioned peptides to treat inflammatory diseases. Formula (I), [ES] La invención se refiere a péptidos de fórmula general S, donde el extremo carboxilo terminal (D-Alanina, D-Aia) es reemplazado por un amlnoalcohol análogo. La invención también se refiere a su procedimiento de síntesis y al uso de los péptidos mencionados para el tratamiento de enfermedades inflamatorias. Formula (I), [FR] L'invention concerne des peptides de formule générale S, où l'extrémité carboxyle terminale (D-alanine, D-ala) est remplacée par un amino-alcool analogue. L'invention concerne également son procédé de synthèse et l'utilisation des peptides mentionnés pour le traitement de maladies inflammatoires. Formule (I)

La invención se refiere a péptidos de fórmula general I, donde el extremo carboxilo terminal (D-Alanina, D-Ala) es reemplazado por un aminoalcohol análogo. La invención también se refiere a su procedimiento de síntesis y al uso de los péptidos mencionados para el tratamiento de enfermedades inflamatorias

Inhibition of Leishmania infantum trypanothione disulfide reductase (LiTryR) by disruption of its homodimeric interface has proved to be an alternative and unexploited strategy in the search for novel antileishmanial agents. Proof of concept was first obtained by peptides and peptidomimetics. Building on previously reported dimerization disruptors containing an imidazole-phenyl-thiazole scaffold, we now report a new 1,2,3-triazole-based chemotype that yields noncompetitive, slow-binding inhibitors of LiTryR. Several compounds bearing (poly)aromatic substituents dramatically improve the ability to disrupt LiTryR dimerization relative to reference imidazoles. Molecular modeling studies identified an almost unexplored hydrophobic region at the interfacial domain as the putative binding site for these compounds. A subsequent structure-based design led to a symmetrical triazole analogue that displayed even more potent inhibitory activity over LiTryR and enhanced leishmanicidal activity. Remarkably, several of these novel triazole-bearing compounds were able to kill both extracellular and intracellular parasites in cell cultures.

The present invention refers to new compounds useful in the treatment of leishmaniasis and, more particularly, to a series of 5-6-5 triazole-phenyl-thiazole heterocycles capable of inhibiting both activity and dimerization of L. infantum Try R in enzymatic assays at low micromolar concentrations and endowed with potent in vitro activity against promastigote and amastigote forms of Leishmania which indicates a good permeability across the plasma membrane ofthe parasites

Se describen nuevos inhibidores de fusión dirigidos a la Hemaglutinina del virus influenza