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Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity

Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include liposomal formulation or deoxycholate salt of amphotericin B, which has been associated with various complications and severe side effect...

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Autores principales: Chakrabarti, Amrita, Narayana, Chintam, Joshi, Nishant, Garg, Swati, Garg, Lalit C., Ranganathan, Anand, Sagar, Ram, Pati, Soumya, Singh, Shailja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115111/
https://www.ncbi.nlm.nih.gov/pubmed/35601095
http://dx.doi.org/10.3389/fcimb.2022.803048
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author Chakrabarti, Amrita
Narayana, Chintam
Joshi, Nishant
Garg, Swati
Garg, Lalit C.
Ranganathan, Anand
Sagar, Ram
Pati, Soumya
Singh, Shailja
author_facet Chakrabarti, Amrita
Narayana, Chintam
Joshi, Nishant
Garg, Swati
Garg, Lalit C.
Ranganathan, Anand
Sagar, Ram
Pati, Soumya
Singh, Shailja
author_sort Chakrabarti, Amrita
collection PubMed
description Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include liposomal formulation or deoxycholate salt of amphotericin B, which has been associated with various complications and severe side effects. Encouraged from the recent marked antimalarial effects from plant-derived glycosides, in this study, we have exploited a green chemistry-based approach to chemically synthesize a library of diverse glycoside derivatives (Gly1–12) and evaluated their inhibitory efficacy against the AG83 strain of Leishmania donovani. Among the synthesized glycosides, the in vitro inhibitory activity of Glycoside-2 (Gly2) (1.13 µM IC50 value) on L. donovani promastigote demonstrated maximum cytotoxicity with ~94% promastigote death as compared to amphotericin B that was taken as a positive control. The antiproliferative effect of Gly2 on promastigote encouraged us to analyze the structure–activity relationship of Gly2 with Gp63, a zinc metalloprotease that majorly localizes at the surface of the promastigote and has a role in its development and multiplication. The result demonstrated the exceptional binding affinity of Gly2 toward the catalytic domain of Gp63. These data were thereafter validated through cellular thermal shift assay in a physiologically relevant cellular environment. Mechanistically, reduced multiplication of promastigotes on treatment with Gly2 induces the destabilization of redox homeostasis in promastigotes by enhancing reactive oxygen species (ROS), coupled with depolarization of the mitochondrial membrane. Additionally, Gly2 displayed strong lethal effects on infectivity and multiplication of amastigote inside the macrophage in the amastigote–macrophage infection model in vitro as compared to amphotericin B treatment. Gp63 is also known to bestow protection against complement-mediated lysis of parasites. Interestingly, Gly2 treatment enhances the complement-mediated lysis of L. donovani promastigotes in serum physiological conditions. In addition, Gly2 was found to be equally effective against the clinical promastigote forms of PKDL strain (IC50 value of 1.97 µM); hence, it could target both VL and PKDL simultaneously. Taken together, this study reports the serendipitous discovery of Gly2 with potent antileishmanial activity and proves to be a novel chemotherapeutic prototype against VL and PKDL.
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spelling pubmed-91151112022-05-19 Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity Chakrabarti, Amrita Narayana, Chintam Joshi, Nishant Garg, Swati Garg, Lalit C. Ranganathan, Anand Sagar, Ram Pati, Soumya Singh, Shailja Front Cell Infect Microbiol Cellular and Infection Microbiology Visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) affect most of the poor populations worldwide. The current treatment modalities include liposomal formulation or deoxycholate salt of amphotericin B, which has been associated with various complications and severe side effects. Encouraged from the recent marked antimalarial effects from plant-derived glycosides, in this study, we have exploited a green chemistry-based approach to chemically synthesize a library of diverse glycoside derivatives (Gly1–12) and evaluated their inhibitory efficacy against the AG83 strain of Leishmania donovani. Among the synthesized glycosides, the in vitro inhibitory activity of Glycoside-2 (Gly2) (1.13 µM IC50 value) on L. donovani promastigote demonstrated maximum cytotoxicity with ~94% promastigote death as compared to amphotericin B that was taken as a positive control. The antiproliferative effect of Gly2 on promastigote encouraged us to analyze the structure–activity relationship of Gly2 with Gp63, a zinc metalloprotease that majorly localizes at the surface of the promastigote and has a role in its development and multiplication. The result demonstrated the exceptional binding affinity of Gly2 toward the catalytic domain of Gp63. These data were thereafter validated through cellular thermal shift assay in a physiologically relevant cellular environment. Mechanistically, reduced multiplication of promastigotes on treatment with Gly2 induces the destabilization of redox homeostasis in promastigotes by enhancing reactive oxygen species (ROS), coupled with depolarization of the mitochondrial membrane. Additionally, Gly2 displayed strong lethal effects on infectivity and multiplication of amastigote inside the macrophage in the amastigote–macrophage infection model in vitro as compared to amphotericin B treatment. Gp63 is also known to bestow protection against complement-mediated lysis of parasites. Interestingly, Gly2 treatment enhances the complement-mediated lysis of L. donovani promastigotes in serum physiological conditions. In addition, Gly2 was found to be equally effective against the clinical promastigote forms of PKDL strain (IC50 value of 1.97 µM); hence, it could target both VL and PKDL simultaneously. Taken together, this study reports the serendipitous discovery of Gly2 with potent antileishmanial activity and proves to be a novel chemotherapeutic prototype against VL and PKDL. Frontiers Media S.A. 2022-05-04 /pmc/articles/PMC9115111/ /pubmed/35601095 http://dx.doi.org/10.3389/fcimb.2022.803048 Text en Copyright © 2022 Chakrabarti, Narayana, Joshi, Garg, Garg, Ranganathan, Sagar, Pati and Singh https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Chakrabarti, Amrita
Narayana, Chintam
Joshi, Nishant
Garg, Swati
Garg, Lalit C.
Ranganathan, Anand
Sagar, Ram
Pati, Soumya
Singh, Shailja
Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity
title Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity
title_full Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity
title_fullStr Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity
title_full_unstemmed Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity
title_short Metalloprotease Gp63-Targeting Novel Glycoside Exhibits Potential Antileishmanial Activity
title_sort metalloprotease gp63-targeting novel glycoside exhibits potential antileishmanial activity
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115111/
https://www.ncbi.nlm.nih.gov/pubmed/35601095
http://dx.doi.org/10.3389/fcimb.2022.803048
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