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Asymmetric peptidomimetics containing L-tartaric acid core inhibit the aspartyl peptidase activity and growth of Leishmania amazonensis promastigotes

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Abstract

Aspartyl-type peptidases are promising chemotherapeutic targets in protozoan parasites. In the present work, we identified an aspartyl peptidase activity from the soluble extract of Leishmania amazonensis promastigotes, which cleaved the fluorogenic peptide 7-methoxycoumarin-4-acetyl-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-amide (cathepsin D substrate) under acidic pH conditions at 37°C, showing a KM of 0.58 μM and Vmax of 129.87 fluorescence arbitrary units/s mg protein. The leishmanial aspartyl peptidase activity was blocked by pepstatin A (IC50 = 6.8 μM) and diazo-acetyl-norleucinemetilester (IC50 = 10.2 μM), two classical aspartyl peptidase inhibitors. Subsequently, the effects of 6 asymmetric peptidomimetics, containing L-tartaric acid core, were tested on both aspartyl peptidase and growth of L. amazonensis promastigotes. The peptidomimetics named 88, 154 and 158 promoted a reduction of 50% on the leishmanial aspartyl peptidase activity at concentrations ranging from 40 to 85 μM, whereas the peptidomimetic 157 was by far the most effective, presenting IC50 of 0.04 μM. Furthermore, the peptidomimetics 157 and 154 reduced the parasite proliferation in a dose-dependent manner, displaying IC50 values of 33.7 and 44.5 µM, respectively. Collectively, the peptidomimetic 157 was the most efficient compound able to arrest both aspartyl peptidase activity and leishmanial proliferation, which raises excellent perspectives regarding its use against this human pathogenic protozoan.

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Authors and Affiliations

  1. Laboratório de Investigação de Peptidases, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    André L. S. Santos, Filipe P. Matteoli, Leandro S. Sangenito & Marta H. Branquinha

  2. Programa de Pós-Graduação em Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    André L. S. Santos

  3. Instituto Federal de Educação Ciência e Tecnologia do Rio de Janeiro, Campus Rio de Janeiro, Rio de Janeiro, Brazil

    Bruno A. Cotrim & Gabriel O. Resende

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  1. André L. S. Santos
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  2. Filipe P. Matteoli
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  3. Leandro S. Sangenito
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  4. Marta H. Branquinha
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  5. Bruno A. Cotrim
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  6. Gabriel O. Resende
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Correspondence to André L. S. Santos.

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Santos, A.L.S., Matteoli, F.P., Sangenito, L.S. et al. Asymmetric peptidomimetics containing L-tartaric acid core inhibit the aspartyl peptidase activity and growth of Leishmania amazonensis promastigotes. Acta Parasit. 63, 114–124 (2018). https://doi.org/10.1515/ap-2018-0013

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