The emergence of drug resistance is a major concern for combating against Cutaneous Leishmaniasis, a neglected tropical disease affecting 98 countries including India. Miltefosine is the only oral drug available for the disease and Miltefosine transporter proteins play a pivotal role in the emergence of drug-resistant Leishmania major. The cause of resistance is less accumulation of drug inside the parasite either by less uptake of the drug due to a decrease in the activity of P4ATPase–CDC50 complex or by increased efflux of the drug by P-glycoprotein (P-gp, an ABC transporter). In this paper, we are trying to allosterically modulate the behavior of resistant parasite (L. major) towards its sensitivity for the existing drug (Miltefosine, a phosphatidylcholine analog). We have used computational approaches to deal with the conservedness of the proteins and apparently its three-dimensional structure prediction through ab initio modeling. Long scale membrane-embedded molecular dynamics simulations were carried out to study the structural interaction and stability. Parasite-specific motifs of these proteins were identified based on the machine learning technique, against which a peptide library was designed. The protein–peptide docking shows good binding energy of peptides Pg5F, Pg8F and PC2 with specific binding to the motifs. These peptides were tested both in vitro and in vivo, where Pg5F in combination with PC2 showed 50–60% inhibition in resistant L. major's promastigote and amastigote forms and 80–90% decrease in parasite load in mice. We posit a model system wherein the data provide sufficient impetus for being novel therapeutics in order to counteract the drug resistance phenotype in Leishmania parasites.
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May 2020
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Cover Image
The cover image shows high resolution of the 20 lowest energy structures of kringle 2 of human plasminogen to AGL55-NS88.2 (top) and KT155-SS1448 (bottom). To learn more about this, see the article by Qiu and colleagues (pp. 1613–1630). The image was provided by Francis J. Castellino.
Research Article|
May 29 2020
Computationally designed synthetic peptides for transporter proteins imparts allostericity in Miltefosine resistant L. major
Ritika Kabra;
Ritika Kabra
National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
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Prajakta Ingale;
Prajakta Ingale
National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
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Shailza Singh
National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
Correspondence: Shailza Singh (singhs@nccs.res.in)
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Publisher: Portland Press Ltd
Received:
March 02 2020
Revision Received:
May 07 2020
Accepted:
May 11 2020
Accepted Manuscript online:
May 11 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (10): 2007–2026.
Article history
Received:
March 02 2020
Revision Received:
May 07 2020
Accepted:
May 11 2020
Accepted Manuscript online:
May 11 2020
Citation
Ritika Kabra, Prajakta Ingale, Shailza Singh; Computationally designed synthetic peptides for transporter proteins imparts allostericity in Miltefosine resistant L. major. Biochem J 29 May 2020; 477 (10): 2007–2026. doi: https://doi.org/10.1042/BCJ20200176
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