Phenotypic Screening of Small Molecules with Antimalarial Activity for Three Different Parasitic Life Stages

Abstract Plasmodial heat shock protein 70 (Hsp70) chaperones represent a promising new class of antimalarial drug targets because of the important roles they play in the survival and pathogenesis of the malaria parasite Plasmodium falciparum. This study assessed a set of small molecules (lapachol, bromo-β-lapachona and malonganenones A, B and C) as potential modulators of two biologically important plasmodial Hsp70s, the parasite-resident PfHsp70-1 and the exported PfHsp70-x. Compounds of interest were assessed for modulatory effects on the steady-state basal and heat shock protein 40 (Hsp40)-stimulated ATPase activities of PfHsp70-1, PfHsp70-x and human Hsp70, as well as on the protein aggregation suppression activity of PfHsp70-x. The antimalarial marine alkaloid malonganenone A was of particular interest, as it was found to have limited cytotoxicity to mammalian cell lines and exhibited the desired properties of an effective plasmodial Hsp70 modulator. This compound was found to inhibit plasmodial and not human Hsp70 ATPase activity (Hsp40-stimulated), and hindered the aggregation suppression activity of PfHsp70-x. Furthermore, malonganenone A was shown to disrupt the interaction between PfHsp70-x and Hsp40. This is the first report to show that PfHsp70-x has chaperone activity, is stimulated by Hsp40 and can be specifically modulated by small molecule compounds.

Download Full-text

From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

Molecules ◽

10.3390/molecules25235702 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5702

Author(s):

Quentin T. L. Pasquer ◽

Ioannis A. Tsakoumagkos ◽

Sascha Hoogendoorn

Keyword(s):

Small Molecules ◽

Chemical Biology ◽

Target Identification ◽

Biologically Active ◽

Phenotypic Screening ◽

Biological Processes ◽

Chemical Probes ◽

Target Deconvolution ◽

Cellular Target ◽

Screening Approaches

Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.

Download Full-text

Streamlining Chemical Probe Discovery: Libraries of “Fully Functionalized” Small Molecules for Phenotypic Screening

Angewandte Chemie International Edition ◽

10.1002/anie.201207306 ◽

2012 ◽

Vol 52 (5) ◽

pp. 1368-1370 ◽

Cited By ~ 12

Author(s):

Julian Oeljeklaus ◽

Farnusch Kaschani ◽

Markus Kaiser

Keyword(s):

Small Molecules ◽

Phenotypic Screening ◽

Chemical Probe

Download Full-text

Chemical genetics approach to drug discovery by diversity-oriented synthesis (DOS) of peptidomimetics

Pure and Applied Chemistry ◽

10.1351/pac-con-10-09-30 ◽

2011 ◽

Vol 83 (3) ◽

pp. 687-698 ◽

Cited By ~ 5

Author(s):

Andrea Trabocchi ◽

Duccio Cavalieri ◽

Antonio Guarna

Keyword(s):

Drug Discovery ◽

Small Molecules ◽

Anticancer Agents ◽

Structural Diversity ◽

Chemical Genetics ◽

Biological Evaluation ◽

Phenotypic Screening ◽

Diversity Oriented Synthesis ◽

Biological Phenotype ◽

Lead Generation

Chemical genetics, which relies on selecting small molecules for their ability to induce a biological phenotype or to interact with a particular gene product, is a new powerful tool for lead generation in drug discovery. Accordingly, diversity-oriented synthesis (DOS) of small-molecule peptidomimetics gives access to collections of new chemotypes bearing high structural diversity. Biological evaluation using cell growth as a phenotypic screening on Saccharomyces cerevisiae deletant strains is a powerful tool to identify new chemotypes as hit compounds in the discovery of new antifungal and anticancer agents, and also in the dissection of their mode of action. Our contribution in this field focused on the screening of morpholine-based peptidomimetic collections toward yeast deletant strains, which provided the identification of new chemotypes involved in mitochondria metabolism and respiration.

Download Full-text

Water-Compatible Cycloadditions of Oligonucleotide-Conjugated Strained Allenes for DNA-Encoded Library Synthesis

10.26434/chemrxiv.11342471.v1 ◽

2019 ◽

Author(s):

Matthias V. Westphal ◽

Liam Hudson ◽

Jeremy W. Mason ◽

Frédéric J. Zécri ◽

Karin Briner ◽

...

Keyword(s):

Drug Discovery ◽

Small Molecules ◽

Reactive Intermediates ◽

Phenotypic Screening ◽

Library Synthesis ◽

Topographic Features ◽

Mild Conditions ◽

Single Precursor ◽

Activated Olefins ◽

Early Drug

DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-discovery efforts. Combinatorial syntheses of such libraries require water- and DNA-compatible reactions, and the paucity of these reactions currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with activated olefins, 1,3-dipoles and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-barcoded compounds exhibit unprecedented ring and topographic features—related to elements found to be powerful in phenotypic screening.

Download Full-text

Development of a chemogenomics library for phenotypic screening

Journal of Cheminformatics ◽

10.1186/s13321-021-00569-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Bryan Dafniet ◽

Natacha Cerisier ◽

Batiste Boezio ◽

Anaelle Clary ◽

Pierre Ducrot ◽

...

Keyword(s):

Small Molecules ◽

Drug Target ◽

Drug Targets ◽

Chemical Biology ◽

Target Identification ◽

Biological Effects ◽

Phenotypic Screening ◽

High Content Imaging ◽

Advanced Technologies ◽

System Pharmacology

AbstractWith the development of advanced technologies in cell-based phenotypic screening, phenotypic drug discovery (PDD) strategies have re-emerged as promising approaches in the identification and development of novel and safe drugs. However, phenotypic screening does not rely on knowledge of specific drug targets and needs to be combined with chemical biology approaches to identify therapeutic targets and mechanisms of actions induced by drugs and associated with an observable phenotype. In this study, we developed a system pharmacology network integrating drug-target-pathway-disease relationships as well as morphological profile from an existing high content imaging-based high-throughput phenotypic profiling assay known as “Cell Painting”. Furthermore, from this network, a chemogenomic library of 5000 small molecules that represent a large and diverse panel of drug targets involved in diverse biological effects and diseases has been developed. Such a platform and a chemogenomic library could assist in the target identification and mechanism deconvolution of some phenotypic assays. The usefulness of the platform is illustrated through examples.

Download Full-text