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Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.

ABSTRACT: The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

SUBMITTER: Thomas MG

PROVIDER: S-EPMC6407917 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.

Thomas Michael G MG De Rycker Manu M Ajakane Myriam M Albrecht Sébastian S Álvarez-Pedraglio Ana Isabel AI Boesche Markus M Brand Stephen S Campbell Lorna L Cantizani-Perez Juan J Cleghorn Laura A T LAT Copley Royston C B RCB Crouch Sabrinia D SD Daugan Alain A Drewes Gerard G Ferrer Santiago S Ghidelli-Disse Sonja S Gonzalez Silvia S Gresham Stephanie L SL Hill Alan P AP Hindley Sean J SJ Lowe Rhiannon M RM MacKenzie Claire J CJ MacLean Lorna L Manthri Sujatha S Martin Franck F Miguel-Siles Juan J Nguyen Van Loc VL Norval Suzanne S Osuna-Cabello Maria M Woodland Andrew A Patterson Stephen S Pena Imanol I Quesada-Campos Maria Teresa MT Reid Iain H IH Revill Charlotte C Riley Jennifer J Ruiz-Gomez Jose Ramon JR Shishikura Yoko Y Simeons Frederick R C FRC Smith Alasdair A Smith Victoria C VC Spinks Daniel D Stojanovski Laste L Thomas John J Thompson Stephen S Underwood Tim T Gray David W DW Fiandor Jose M JM Gilbert Ian H IH Wyatt Paul G PG Read Kevin D KD Miles Timothy J TJ

Journal of medicinal chemistry 20181220 3

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance ...[more]

PMID: 30570265

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Project description:IntroductionTo sustain the achievement of kala-azar elimination program (KEP), early detection and treatment of the visceral leishmaniasis (VL) cases and associated modalities such as treatment failure (TF), relapse VL (RVL), and Post-kala-azar dermal leishmaniasis (PKDL) is the cornerstone. A predictive biomarker for VL development and related complications could also play a crucial role in curtailing disease incidence and transmission. Investigations to find a biomarker with prospective capabilities are, however, scarce. Using samples and known clinical outcomes generated within two previous longitudinal cohort studies, we aimed to determine if fluctuations in serum anti-rK39 antibody levels could provide such predictive value.Materials and methodsSerum samples collected at four different time points (Baseline, 12, 18, and 24 months) from 16 patients who had developed VL within the monitoring period and 15 of their asymptomatic healthy controls counterparts were investigated. To investigate potential prediction of VL related complications, serum samples of 32 PKDL, 10 RVL, 07 TF, and 38 cured VL from a single dose AmBisome trial were analyzed. Of this second panel, all patients were monitored for 5 years and sera were collected at four time points (Baseline then 1, 6, and 12 months after treatment). The level of anti-rK39 antibodies in archived samples was measured by a semi-quantitative ELISA.ResultsThe mean antibody level was significantly higher in VL patients compared to their asymptomatic healthy counterparts at each time point. Likewise, we observed a trend toward elevations in antibody levels for PKDL, RVL, TF relative to the reducing levels observed in cured VL. Receiver operating characteristic (ROC) analysis found a promising predictive power of rK39 antibody levels to reveal progression from asymptomatic Leishmania donovani infection stage to VL, defined as 87.5% sensitive and 95% specific. Following treatment, rk39 antibody notably showed 100% sensitivity and 95% specificity in predicting TF.ConclusionOur data indicate that the relative quantity of serum anti-rK39 antibody has promise within either a predictive or prognostic algorithm for VL and VL-related modalities. These could enable VL control programs to implement more effective measures to eliminate the disease. Further research is, however, imperative to standardize the rK39 antibody ELISA between sites prior to broader use.

Dataset Information

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.

Publications

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.

Similar Datasets

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