Biology subjects

Laleu, B.

Publications and source records attributed to Laleu, B..

8 recordsLinked to original sources

bioRxiv2025

Identification of α-azacyclic acetamide-based inhibitors of P. falciparum Na+ pump (PfATP4) with fast-killing asexual blood-stage antimalarial activity by phenotypic screening

Malaria treatments are compromised by drug resistance, creating an urgent need to discover new drugs. We used a phenotypic high-throughput screening (HTS) platform to identify new antimalarials, uncovering three related pyrrole-, indole-, and indoline-based series with a shared -azacyclic acetamide core. These compounds showed fast-killing activity on asexual blood-stage Plasmodium falciparum parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na+ regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the P. falciparum Na+ pump (PfATP4). PfATP4 is localized to the parasite plasma membrane and is essential for maintaining a low cytosolic Na+ concentration. Resistance selections on P. falciparum parasites with two -azacyclic acetamide analogs identified mutations in PfATP4, and cross-resistance was observed across the -azacyclic acetamides and KAE609, confirming PfATP4 as the target. PfATP4 is a well-established antimalarial target, and identification of additional PfATP4 inhibitors provides alternative avenues to disrupt its function.

microbiology↗

bioRxiv2025

Discovery and structure-activity relationship analysis of 2-Pyridyl Thienopyrimidine derivatives as promising therapeutic candidates for the treatment of Buruli ulcer

Mycobacterium ulcerans, the bacterium causing Buruli ulcer (BU), can potentially develop resistance to existing antibiotics (rifampicin - clarithromycin/ moxifloxacin), underscoring the need for new antimycobacterial treatments. This study screened the Pathogen Box from Medicines for Malaria Venture (MMV) to identify M. ulcerans inhibitors. Four hit compounds were found, including the 2-(6-methylpyridin-2-yl)-N-(pyrimidin-4-yl)thieno[3,2-d]pyrimidin-4-amine MMV688122 as a novel anti-M. ulcerans chemotype. Synthesis of structural analogues of MMV688122 allowed the identification of 2-(4-methylpyridin-2-yl)-N-(pyrimidin-4-yl)thieno[3,2-d]pyrimidin-4-amine MMV1578877 as the most potent, with submicromolar activity. Importantly, this analogue was non-cytotoxic up to 100 {micro}M in human fibroblasts. Structure-activity relationship (SAR) studies indicated the crucial role of the methylpyridin-2-yl group in inhibiting M. ulcerans and the possibility to replace the thienopyrimidine core by a quinazoline. While MMV1578877 showed better metabolic stability than MMV688122, further improvement and testing in real-world M. ulcerans clinical isolates are still required. Further metabolite identification and SAR data should guide the optimization of this novel chemotype to enable in vivo testing. Author SummaryBuruli ulcer is a neglected tropical disease that causes severe skin ulcers and long-term disability, mostly affecting people in remote African communities. Current treatments rely on antibiotics that are not always effective and may lead to resistance. In this study, we searched for new drug candidates by testing a library of compounds provided by the Medicines for Malaria Venture (MMV). We discovered a promising new chemical family that can kill the bacteria responsible for Buruli ulcer in the lab. One compound, in particular, showed strong activity without harming human cells. This compound also showed better stability and effectiveness. These findings bring us closer to developing a new, safer, and more effective treatment for Buruli ulcer.

pharmacology and toxicology↗

bioRxiv2022

A fast-killing tyrosine amide ((S)-SW228703) with blood and liver-stage antimalarial activity associated with the Cyclic Amine Resistance Locus (PfCARL)

Current malaria treatments are threatened by drug resistance and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their target(s) are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for activity of (S)-SW703, suggesting differences in mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity on multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.

microbiology↗

bioRxiv2022

A small-molecule myosin inhibitor as a targeted multi-stage antimalarial

Malaria is a devastating disease that resulted in an estimated 627,000 deaths in 2020. About 80% of those deaths were among children under the age of five. Our approach is to develop small molecule inhibitors against cytoskeletal targets that are vital components of parasite function, essential at multiple stages of parasite infection, can be targeted with high specificity, and are highly druggable. Here we describe KNX-115, which inhibits purified Plasmodium falciparum myosin A (PfMyoA) actin-activated ATPase with a potency in the 10s of nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 inhibits the blood and liver stages of Plasmodium with an EC50 of about 100 nanomolar, with negligible liver cell toxicity. In addition, KNX-115 inhibits sporozoite cell traversal and blocks the gametocyte to oocyst conversion in the mosquito. KNX-115 displays a similar killing profile to pyrimethamine and parasites are totally killed after 96 hours of treatment. In line with its novel mechanism of action, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials. In vitro evolution data likely suggests a refractory potential of KNX-115 in developing parasite resistance.

pharmacology and toxicology↗

bioRxiv2022

Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum, using a nano luciferase reporter read-out

A central challenge of antimalarial therapy is the emergence of resistance to the components of artemisinin-based combination therapies (ACTs) and the urgent need for new drugs acting through novel mechanism of action. Over the last decade, compounds identified in phenotypic high throughput screens (HTS) have provided the starting point for six candidate drugs currently in the Medicines for Malaria Venture (MMV) clinical development portfolio. However, the published screening data which provided much of the new chemical matter for malaria drug discovery projects have been extensively mined. Here we present a new screening and selection cascade for generation of hit compounds active against the blood stage of Plasmodium falciparum. In addition, we validate our approach by testing a library of 141,786 compounds not reported earlier as being tested against malaria. The Hit Generation Library 1 (HGL1) was designed to maximise the chemical diversity and novelty of compounds with physicochemical properties associated with potential for further development. A robust HTS cascade containing orthogonal efficacy and cytotoxicity assays, including a newly developed and validated nanoluciferase-based assay was used to profile the compounds. 75 compounds (Screening Active hit rate of 0.05%) were identified meeting our stringent selection criteria of potency in drug sensitive (NF54) and drug resistant (Dd2) parasite strains (IC50 [≤] 2 {micro}M), rapid speed of action and cell viability in HepG2 cells (IC50 [≥] 10 {micro}M). Following further profiling, 33 compounds were identified that meet the MMV Confirmed Active profile and are high quality starting points for new antimalarial drug discovery projects.

microbiology↗

bioRxiv2022

Rudimentary Structure-Activity-Relationship study of the MMV Pathogen Box compound MMV675968 (2,4-diaminoquinazoline) unveils novel inhibitors of Trypanosoma brucei brucei DHFR enzyme

New drugs are urgently needed for the treatment of human African trypanosomiasis (HAT). In line with our quest for dihydrofolate reductase (DHFR) inhibitors in trypanosomes, a small library of analogs of the antitrypanosomal hit (MMV675968) available at MMV as solid materials was screened for antitrypanosomal activity. In silico confirmation of two potent antitrypanosomal analogs as inhibitors of DHFR was achieved, together with elucidation of other antitrypanosomal modes of action. Overall, two analogs of the diaminoquinazoline derivative, MMV675968 reputed to inhibit the enzyme DHFR, displayed approximately 40-fold and 60-fold more potency and selectivity than the parent hit, respectively (MMV1578445 (10): IC50 = 0.045 {micro}M, SI=1737; MMV1578467 (7): IC50 = 0.06 {micro}M; SI=412). Analogs 7 and 10 were also strong binders of the DHFR enzyme, in all their accessible protonation states, and interacted with key DHFR ligand recognition residues Val32, Asp54, and Ile160. MMV1578445 (10) portrayed fast and irreversible trypanosomes growth arrest after 72 h and 4 h at IC99. Analogs 7 and 10 induced ferric iron reduction and DNA fragmentation or apoptosis induction, respectively. The two potent analogs endowed with suitable physicochemical properties are good candidates for further deciphering their potential as starting points for new drug development for HAT. Author summaryAfrican trypanosomiasis is a disease caused by parasites of the Trypanosoma brucei species which affect both humans and animals. We have adopted the fast-track drug repurposing approach to determine the antitrypanosomal activity of the open access MMV Pathogen Box compound library. The compound 2,4-diaminoquinazoline (MMV675998), known as a dihydrofolate reductase (DHFR) inhibitor was identified. Rudimentary structure-activity relationship investigation of this compound unveiled two highly active and selective derivatives MMV1578445 and MMV1578467 which were found to strongly inhibit the Trypanosoma brucei dihydrofolate reductase enzyme in silico. Besides, we demonstrated that analogues MMV1578445 and MMV1578467 could respectively reduce intrinsic ferric iron and induce apoptosis in trypanosomes. The two identified inhibitors of trypanosomes qualify as potential drug candidates that could be useful for future development as novel antitrypanosomal drugs.

pharmacology and toxicology↗

bioRxiv2019

Screening the MMV Open Access Pathogen box unveils novel and potent inhibitors of Amoebiasis agent: Entamoeba histolytica

Amoebiasis caused by the protozoan parasite Entamoeba histolytica remains a major public health hazard, as being the second cause of death among parasitic infections. Although currently prescribed drugs have shown to be effective in the treatment of amoebiasis, side effects and emergence of parasites resistance prompted the search for novel drug to control this disease. In this regard, the Medicines for Malaria Venture (MMV) Pathogen Box library of selected compounds was screened to identify anti-Entamoeba histolytica agents using the resazurin based fluorescence assay. Overall, the results revealed three novel anti-Entamoeba histolytica scaffolds with low micromolar activity including MMV675968 (IC50 = 2.10 {micro}M), MMV688179 (IC50 = 2.38 {micro}M) and MMV688844 (IC50 = 5.63 {micro}M). Structure-Activity-Relationship (SAR) studies led to identification of two analogs [~]100 fold more potent and selective than the original hit compound 1 (MMV675968): 1k (IC50 = 0.043 {micro}M) and 1l (IC50 = 0.055 {micro}M). Predictive analysis using Maestro 11.6 suggested that these hit compounds possess acceptable physicochemical and metabolism properties. These lead compounds are therefore good starting points for lead optimization studies towards identification of drug candidate against amoebiasis.\n\nAuthor SummaryDiarrhoea is a leading cause of death for millions of children worldwide. One of the top 15 causes of severe diarrhoea is Entamoeba histolytica, causing amoebiasis. What makes E. histolytica dangerous is its ability to disseminate easily through a given population via contaminated food and water supplies. Moreover, E. histolytica is quite comfortable in the environment, difficult to kill with chorine and infect people at a very low dose, making it a priority pathogen to eradicate. Many drugs have been developed so far to cure this infection. However, they are not efficient enough to control the disease due to pathogen resistance that is becoming a big issue. In addition to that, almost all the drugs in use are highly toxic to human causing several side effects upon medications. Therefore, new, more efficient and less toxic drugs are urgently needed for the better management of amoebiasis. Since the development of a new drug takes years, repurposing existing drugs has been shown to shortcut the process and boost the discovery rate of new medicines. Using this same approach, we have identified two compounds that potently inhibit E. histolytica and are nontoxic that can enter the drug discovery pipeline for new amoebicidal drug development. Moreover, these new inhibitors could also serve as starting points for the synthesis of a library of amoebicidal compounds.

pharmacology and toxicology↗

bioRxiv2018

Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.\n\nAuthor summaryMycetoma is a poverty-associated disease that was recently recognised as a neglected tropical disease by the World Health Organisation (WHO). This disease can be caused by either bacteria (actinomycetoma) or fungi (eumycetoma). The most common causative agent of mycetoma is the fungus Madurella mycetomatis. Actinomycetoma can be easily treated, but for eumycetoma, the current and only antifungal drug used is only able to successfully treat 30% of patients. Treatment often involves prolonged medication use and amputation of the affected area. This disease is disfiguring and is a social stigma for patients in endemic countries. To improve treatment for patients, we have looked at over 800 diverse drug-like molecules and compounds in hope to develop new drugs in this study. We have identified 215 compounds with activity against M. mycetomatis in vitro and several in vivo with our Galleria mellonella larvae model. We have chosen an open source approach with this study and placed our findings in an online database and made it available to the public. We invite the global scientific community to participate in our study and contribute as equal partners as long as an open source approach is held in hopes to fast track and boost drug discovery for Eumycetoma.

pharmacology and toxicology↗