Selective anti-Leishmanial Strathclyde minor groove binders using an N-oxide tail group modification

Marina C. Perieteanu; Leah M.C. McGee; Craig D. Shaw; Donna S. MacMillan; Abedawn I. Khalaf; Kirsten Gillingwater; Rebecca Beveridge; Katharine C. Carter; Colin J. Suckling; Fraser J. Scott

doi:10.3390/ijms231911912

Selective anti-Leishmanial Strathclyde minor groove binders using an N-oxide tail group modification

Marina C. Perieteanu, Leah M.C. McGee, Craig D. Shaw, Donna S. MacMillan, Abedawn I. Khalaf, Kirsten Gillingwater, Rebecca Beveridge, Katharine C. Carter, Colin J. Suckling, Fraser J. Scott

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Abstract

The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani, and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics.

Original language	English
Article number	11912
Number of pages	16
Journal	International Journal of Molecular Sciences
Volume	23
Issue number	19
Early online date	7 Oct 2022
DOIs	https://doi.org/10.3390/ijms231911912
Publication status	Published - 7 Oct 2022

Funding

This work was, in part, supported by an EPSTC DTP award to the University of Strathclyde, EP/T517938/1 (2432483), and by a Wellcome Trust Seed Award awarded to F.J.S. (210103/A/18/Z). R.B. was supported by a UKRI FLF (MR/T020970/1).

Keywords

leishmaniasis
minor groove binders
S-MGB
DNA

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Perieteanu-etal-IJMS-2022-Selective-anti-Leishmanial-Strathclyde-minor-groove-bindersFinal published version, 955 KBLicence: CC BY 4.0

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Perieteanu, M. C., McGee, L. M. C., Shaw, C. D., MacMillan, D. S., Khalaf, A. I., Gillingwater, K., Beveridge, R., Carter, K. C., Suckling, C. J., & Scott, F. J. (2022). Selective anti-Leishmanial Strathclyde minor groove binders using an N-oxide tail group modification. International Journal of Molecular Sciences, 23(19), Article 11912. https://doi.org/10.3390/ijms231911912

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title = "Selective anti-Leishmanial Strathclyde minor groove binders using an N-oxide tail group modification",

abstract = "The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani, and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics.",

keywords = "leishmaniasis, minor groove binders, S-MGB, DNA",

author = "Perieteanu, {Marina C.} and McGee, {Leah M.C.} and Shaw, {Craig D.} and MacMillan, {Donna S.} and Khalaf, {Abedawn I.} and Kirsten Gillingwater and Rebecca Beveridge and Carter, {Katharine C.} and Suckling, {Colin J.} and Scott, {Fraser J.}",

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AU - Shaw, Craig D.

AU - MacMillan, Donna S.

AU - Khalaf, Abedawn I.

AU - Gillingwater, Kirsten

AU - Beveridge, Rebecca

AU - Carter, Katharine C.

AU - Suckling, Colin J.

AU - Scott, Fraser J.

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AB - The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani, and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics.

KW - leishmaniasis

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KW - S-MGB

KW - DNA

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ER -

Selective anti-Leishmanial Strathclyde minor groove binders using an N-oxide tail group modification

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