Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review

Abstract

Leishmaniases are a group of vector-borne diseases caused by infection with the protozoan parasites Leishmania spp. Some of them, such as Mediterranean visceral leishmaniasis, are zoonotic diseases transmitted from vertebrate to vertebrate by a hematophagous insect, the sand fly. As there is an endemic in more than 90 countries worldwide, this complex and major health problem has different clinical forms depending on the parasite species involved, with the visceral form being the most worrying since it is fatal when left untreated. Nevertheless, currently available antileishmanial therapies are significantly limited (low efficacy, toxicity, adverse side effects, drug-resistance, length of treatment, and cost), so there is an urgent need to discover new compounds with antileishmanial activity, which are ideally inexpensive and orally administrable with few side effects and a novel mechanism of action. Therefore, various powerful approaches were recently applied in many interesting antileishmanial drug development programs. The objective of this review is to focus on the very first step in developing a potential drug and to identify the exploratory methods currently used to screen in vitro hit compounds and the challenges involved, particularly in terms of harmonizing the results of work carried out by different research teams. This review also aims to identify innovative screening tools and methods for more extensive use in the drug development process.

Exploring direct and indirect targets of current antileishmanial drugs using a novel thermal proteomics profiling approach

“…One of the major bottlenecks in drug discovery is the identification of the molecular targets of a compound ( Fernández-Prada et al., 2019 ; Cohen and Azas, 2021 ), which, if not fully elucidated, hinders subsequent structure-activity relationship studies that have the potential to contribute to drug optimization and drug development ( Terstappen et al., 2007 ). While proteomic-based approaches have become a cornerstone in the study of MoA and MoDR in Leishmania parasites, there remain important knowledge gaps to fill before these mechanisms are holistically understood ( Fernandez-Prada et al., 2018b ; Bhattacharya et al., 2020 ; Douanne et al., 2020a ).…”

Paving the Way: Contributions of Big Data to Apicomplexan and Kinetoplastid Research

“…Bioluminescent reporter lines of Leishmania spp. have been used to monitor parasite viability in the context of drug and vaccine screening ( Caridha et al., 2017 ; Álvarez-Velilla et al., 2019 ; Mendes Costa et al., 2019 ; Agostino et al., 2020 ; Cohen and Azas, 2021 ), but to our knowledge, not within the context of ‘omics’ screens.…”

Flavonoid Derivatives as New Potent Inhibitors of Cysteine Proteases: An Important Step toward the Design of New Compounds for the Treatment of Leishmaniasis

“…The Leishmania lifecycle requires the presence of a sand fly vector and a mammalian host that causes the existence of two distinct morphological forms (promastigote and amastigote). Although the amastigote form is found in host cells and is considered the target form of the parasite, its determination of IC50 consists of a time-consuming and laborious procedure and is not suitable for a large-scale screening method [54]. In general, exploratory screening methods designed to accelerate the testing of many compounds are performed on the promastigote form [54,55].…”