Repurposing as a strategy for the discovery of new anti-leishmanials: the-state-of-the-art

Charlton, Rebecca L; Rossi-Bergmann, Bartira; Denny, Paul W.; Steel, Patrick G.

doi:10.1017/s0031182017000993

Cited by 100 publications

(80 citation statements)

References 128 publications

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“…13 Therefore, shortterm strategies such as searching for novel anti-leishmanial leads by phenotypic screening is an important approach to discover and develop drugs against leishmaniasis. [14][15][16] Drug repurposing, compared to development of new drugs, is time efficient and cost effective. 16 The art of drug repurposing usually starts with developing a method for screening and proceeds to hit identification, lead optimization and clinical studies.…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16] Drug repurposing, compared to development of new drugs, is time efficient and cost effective. 16 The art of drug repurposing usually starts with developing a method for screening and proceeds to hit identification, lead optimization and clinical studies. 16 The present study exploits the phenotypic screening technique to identify antileishmanial "hits" from the Pathogen Box (PB) compounds.…”

Section: Introductionmentioning

confidence: 99%

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Leishmania donovani Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture

Tadele¹,

Abay²,

Makonnen³

et al. 2020

DDDT

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Introduction: Leishmaniasis is a collective term used to describe various pathological conditions caused by an obligate intracellular protozoan of the genus Leishmania. It is one of the neglected diseases and has been given minimal attention by drug discovery and development stakeholders to narrow the safety and efficacy gaps of the drugs currently used to treat leishmaniasis. The challenge is further exacerbated by the emergence of drug resistance by the parasites. Methods: Aiming to look for potential anti-leishmanial hits and leads, we screened Medicines for Malaria Venture (MMV) Pathogen Box compounds against clinically isolated Leishmania donovani strain. In this medium-throughput primary screening assay, the compounds were screened against promastigotes, and then against amastigote stages. Results: From the total 400 compounds screened, 35 compounds showed >50% inhibitory activity on promastigotes in the initial screen (1 μM). Out of these compounds, nine showed >70% inhibition, with median inhibitory concentration (IC 50 ) ranging from 12 to 491 nM using the anti-promastigote assay, and from 53 to 704 nM using the intracellular amastigote assay. Identified compounds demonstrated acceptable safety profiles on THP-1 cell lines and sheep red blood cells, and had appropriate physicochemical properties suitable for further drug development. Two compounds (MMV690102 and MMV688262) were identified as leads. The anti-tubercular agent MMV688262 (delamanid) showed a synergistic effect with amphotericin B, indicating the prospect of using this compound for combination therapy. Conclusion: The current study indicates the presence of additional hits which may hold promise as starting points for anti-leishmanial drug discovery and in-depth structure-activity relationship studies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Leishmania donovani Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture

Tadele¹,

Abay²,

Makonnen³

et al. 2020

DDDT

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“…Searching for novel anti-leishmanial leads by phenotypic screening is an important approach to discover and develop drugs against leishmaniasis [12]. Drug repurposing compared to development of new drug is time efficient and cost effective [13]. The art of drug repurposing usually starts with developing a method for screening and goes to hit identification, lead optimization and clinical studies [13].…”

Section: Introductionmentioning

confidence: 99%

“…Drug repurposing compared to development of new drug is time efficient and cost effective [13]. The art of drug repurposing usually starts with developing a method for screening and goes to hit identification, lead optimization and clinical studies [13]. Varieties of screening methods exist, of which the high throughput screening (HTS) techniques has been used to identify hits in undirected massive screening.…”

Section: Introductionmentioning

confidence: 99%

Identification of Leishmania donovani inhibitors from pathogen box compounds of Medicine for Malaria Venture

Tadele

Abay

Makonnen

et al. 2019

Preprint

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Leishmaniasis is a collective term used to describe various pathological conditions caused by an obligate intracellular protozoan of the genus Leishmania. It is one of the neglected diseases and has been given low attention in drug discovery researches to narrow the existing gap in safety and efficacy of the currently used drugs to treat leishmaniasis. The challenge is further exacerbated by the emergence of drug resistance by the parasites. Aiming to look for potential anti-leishmanial hits and leads, we screened MMV Pathogen Box against clinically isolated L. donovani strain. Compounds were screened against promastigote, and then against amastigote stages; of which, 35 compounds showed >50% inhibition on promastigotes in the initial screen (1 μM). Out of these compounds, 9 compounds showed >70% inhibition with median inhibitory concentration (IC 50 ) ranges from 12 nM to 491 nM on anti-promastigote assay and 53 to 704 nM on intracellular amastigote assay. Identified compounds demonstrated good safety on THP-1 cell lines and sheep RBCs, and appropriate physico-chemical property suitable for further drug development. Two compounds (MMV690102 and MMV688262) were identified as lead compounds. Among these compounds, anti-tubercular agent MMV688262 (delamanid) showed synergistic effect with amphotericin B, indicating the prospect of this compound for combination therapy. The current study indicates the presence of additional hits which may hold promise as starting points for anti-leishmanial drug discovery and in-depth structure activity relationship studies. Future works also needs to investigate antiamastigotes activity of remaining 'hits', which were not covered in the present study. | P a g e Authors summaryVisceral leishmaniasis is a major public health problem in endemic regions. Different drugs have been used to treat visceral leishmaniasis. However, the available drugs are either toxic, noncompliance to the patient, painful upon administration, low in efficacy, or costly. New chemical entities that overcome the limitations of existing drugs are therefore desperately needed.Screening of 400 pathogen box compounds against of Leishmania donovani clinical isolate resulted in identification of 35 compounds with >50% inhibition against promastigotes at 1 μM.Out of these compounds, 9 showed >70% inhibition with median inhibitory concentration ranges from 12 nM to 491 nM on anti-promastigote assay, and 53 to 704 nM on intracellular amastigote assay. Our work identified new compounds which hold promise for further drug development.

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“…Drug repositioning is one of the innovative ways commonly utilized to manage leishmaniasis. 4 Here, drugs made for specific indications are used off-label for treatment of other diseases. Amongst many drugs used off-label and reported as effective in cutaneous leishmaniasis is terbinafine.…”

Section: Introductionmentioning

confidence: 99%

A case of cutaneous leishmaniasis successfully treated with oral terbinafine in Kenya

Mawenzi

2018

Int J Res Dermatol

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Leishmaniasis is a tropical disease of the skin and the reticuloendethelial system caused by a parasite of the genus- Leishmania. The disease poses significant psychosocial and public health burdens in endemic areas. Its treatment poses significant challenges considering that new treatment modalities are currently unavailable. The out-dated and toxic antimonial compounds remain the standard treatment. Nevertheless, these agents are mostly unavailable and reports of resistance to these compounds are increasing. Various drugs have therefore been used off label to treat cutaneous leishmaniasis. Terbinafine, an allylamine designed for treatment of fungal infections has been used off label in the treatment cutaneous leishmaniasis in Middle East and India. However, its potential has not been fully exploited in Kenya. This case is reported of a thirteen year old boy, a resident of a leishmaniasis endemic region in Kenya who presented with a symptomless, well demarcated plaque embedded with crusts and papules on his right cheek. Fine needle aspiration cytology revealed leishmania donovani bodies confirming a diagnosis of cutaneous leishmaniasis. He was treated with oral terbinafine 250mg daily for two consecutive months together with topical application of a combination of 10% Chrotamiton + 2% Sulphur cream applied for three consecutive months. A significant improvement evidenced by substantial flattening of the lesion, conspicuous digital image changes and general clinical improvement was noted after 3 months of follow up. This observation endorses oral terbinafine, as an efficacious management of uncomplicated cutaneous leishmaniasis. To limit scarring, an appropriate topical application can be added to oral terbinafine.

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Repurposing as a strategy for the discovery of new anti-leishmanials: the-state-of-the-art

Cited by 100 publications

References 128 publications

<p><em>Leishmania donovani</em> Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture</p>

<p><em>Leishmania donovani</em> Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture</p>

Identification of Leishmania donovani inhibitors from pathogen box compounds of Medicine for Malaria Venture

A case of cutaneous leishmaniasis successfully treated with oral terbinafine in Kenya

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