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Objective: Plasma metabolite profiling has uncovered several nonglycemic markers of incident type 2 diabetes (T2D). We investigated whether such biomarkers provide information about specific aspects of T2D etiology, such as impaired fasting glucose and impaired glucose tolerance, and whether their association with T2D risk varies by race., Research Design and Methods: Untargeted plasma metabolite profiling was performed of participants in the FINRISK 2002 cohort (n = 7,564). Cox regression modeling was conducted to identify metabolites associated with incident T2D during 14 years of follow-up. Metabolites were clustered into pathways using Gaussian graphical modeling. Clusters enriched for T2D biomarkers were further examined for covariation with fasting plasma glucose (FPG), 2-h postchallenge plasma glucose (2hPG), HbA1c, or fasting insulin. Validation analyses and tests of interaction with race were performed in the Atherosclerosis Risk in Communities study., Results: Two clusters of metabolites, representing diacylglycerols (DAGs) and phosphatidylcholines (PCs), contained the largest number of metabolite associations with incident T2D. DAGs associated with increased T2D incidence (hazard ratio [HR] 1.22; 95% CI 1.14-1.30) independent of FPG, HbA1c, and fasting insulin, but not 2hPG. PCs were inversely associated with T2D risk (HR 0.78; 95% CI 0.71-0.85) independent of FPG, 2hPG, HbA1c, and fasting insulin. No significant interaction between DAGs or PCs and race was observed., Conclusions: Fasting DAGs may capture information regarding T2D risk similar to that represented by 2hPG; PCs may capture aspects of T2D etiology that differ from those represented by conventional biomarkers. The direction of effect and strength of DAG and PC associations with incident T2D are similar across European and African Americans., (© 2024 by the American Diabetes Association.)

Surveillance of drug resistance and the discovery of novel targets-key objectives in the fight against malaria-rely on identifying resistance-conferring mutations in Plasmodium parasites. Current approaches, while successful, require laborious experimentation or large sample sizes. To elucidate shared determinants of antimalarial resistance that can empower in silico inference, we examined the genomes of 724 Plasmodium falciparum clones, each selected in vitro for resistance to one of 118 compounds. We identified 1448 variants in 128 recurrently mutated genes, including drivers of antimalarial multidrug resistance. In contrast to naturally occurring variants, those selected in vitro are more likely to be missense or frameshift, involve bulky substitutions, and occur in conserved, ordered protein domains. Collectively, our dataset reveals mutation features that predict drug resistance in eukaryotic pathogens.

The identification of novel drug targets for the purpose of designing small molecule inhibitors is key component to modern drug discovery. In malaria parasites, discoveries of antimalarial targets have primarily occurred retroactively by investigating the mode of action of compounds found through phenotypic screens. Although this method has yielded many promising candidates, it is time- and resource-consuming and misses targets not captured by existing antimalarial compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction and data mining, we systematically assessed the Plasmodium falciparum genome for proteins amenable to target-based drug discovery, identifying 867 candidate targets with evidence of small molecule binding and blood stage essentiality. Of these, 540 proteins showed strong essentiality evidence and lack inhibitors that have progressed to clinical trials. Expert review and rubric-based scoring of this subset based on additional criteria such as selectivity, structural information, and assay developability yielded 67 high priority candidates. This study also provides a genome-wide data resource and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets., Competing Interests: Declarations Competing Interest Statement MKG has an equity interest in and is a cofounder and scientific advisor of VeraChem LLC, and is on the SABs of InCerebro Inc, Denovicon Therapeutics, and Beren Therapeutics. ELF and SPSR are employees of Novartis Pharma AG and may own shares in Novartis Pharma AG. KD holds stock in TropIQ Health Sciences. The rest of authors declare no competing interests.

It is well-accepted that knowledge of a small molecule's target can accelerate optimization. Although chemogenomic databases are helpful resources for predicting or finding compound interaction partners, they tend to be limited and poorly annotated. Furthermore, unlike genes, compound identifiers are often not standardized, and many synonyms may exist, especially in the biological literature, making batch analysis of compounds difficult. Here, we constructed an open-source annotation and target hypothesis prediction tool that explores some of the largest chemical and biological databases, mining these for both common name, synonyms, and structurally similar molecules. We used this Chemical Analysis and Clustering for Target Identification (CACTI) tool to analyze the Pathogen Box collection, an open-source set of 400 drug-like compounds active against a variety of microbial pathogens. Our analysis resulted in 4,315 new synonyms, 35,963 pieces of new information and target prediction hints for 58 members.Scientific contributionsWith the employment of this tool, a comprehensive report with known evidence, close analogs and drug-target prediction can be obtained for large-scale chemical libraries that will facilitate their evaluation and future target validation and optimization efforts., (© 2024. The Author(s).)

In an effort to identify novel compounds with potent inhibition against Toxoplasma gondii, a phenotypic screen was performed utilizing a library of 683 pure compounds derived primarily from terrestrial and marine fungi. An initial screen with a fixed concentration of 5 µM yielded 91 hits with inhibition comparable to an equal concentration of artemisinin. These compounds were then triaged based on known biological and chemical concerns and liabilities. From these, 49 prioritized compounds were tested in a dose response format with T. gondii and human foreskin fibroblasts (HFFs) for cytotoxicity. Ten compounds were identified with an IC 50 less than 150 nM and a selectivity index (SI) greater than 100. An additional eight compounds demonstrated submicromolar IC 50 and SI values equal to or greater than 35. While the majority of these scaffolds have been previously implicated against apicomplexan parasites, their activities in T. gondii were largely unknown. Herein, we report the T. gondii activity of these compounds with chemotypes including xanthoquinodins, peptaibols, heptelidic acid analogs, and fumagillin analogs, with multiple compounds demonstrating exceptional potency in T. gondii and limited toxicity to HFFs at the highest concentrations tested., Importance: Current therapeutics for treating toxoplasmosis remain insufficient, demonstrating high cytotoxicity, poor bioavailability, limited efficacy, and drug resistance. Additional research is needed to develop novel compounds with high efficacy and low cytotoxicity. The success of artemisinin and other natural products in treating malaria highlights the potential of natural products as anti-protozoan therapeutics. However, the exploration of natural products in T. gondii drug discovery has been less comprehensive, leaving untapped potential. By leveraging the resources available for the malaria drug discovery campaign, we conducted a phenotypic screen utilizing a set of natural products previously screened against Plasmodium falciparum . Our study revealed 18 compounds with high potency and low cytotoxicity in T. gondii , including four novel scaffolds with no previously reported activity in T. gondii . These new scaffolds may serve as starting points for the development of toxoplasmosis therapeutics but could also serve as tool compounds for target identification studies using chemogenomic approach., Competing Interests: The authors declare no conflict of interest.

Antimalarial drug discovery has until recently been driven by high-throughput phenotypic cellular screening, allowing millions of compounds to be assayed and delivering clinical drug candidates. In this review, we will focus on target-based approaches, describing recent advances in our understanding of druggable targets in the malaria parasite. Targeting multiple stages of the Plasmodium lifecycle, rather than just the clinically symptomatic asexual blood stage, has become a requirement for new antimalarial medicines, and we link pharmacological data clearly to the parasite stages to which it applies. Finally, we highlight the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY, a web resource developed for the malaria research community that provides open and optimized access to published data on malaria pharmacology., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Chemical genetic approaches have had a transformative impact on discovery of drug targets for malaria but have primarily been used for parasite targets. To identify human pathways required for intrahepatic development of parasite, we implemented multiplex cytological profiling of malaria infected hepatocytes treated with liver stage active compounds. Some compounds, including MMV1088447 and MMV1346624, exhibited profiles similar to cells treated with nuclear hormone receptor (NHR) agonist/antagonists. siRNAs targeting human NHRs, or their signaling partners identified eight genes that were critical for Plasmodium berghei infection. Knockdown of NR1D2, a host NHR, significantly impaired parasite growth by downregulation of host lipid metabolism. Importantly, treatment with MMV1088447 and MMV1346624 but not other antimalarials, phenocopied the lipid metabolism defect of NR1D2 knockdown. Our data underlines the use of high-content imaging for host-cellular pathway deconvolution, highlights host lipid metabolism as a drug-able human pathway and provides new chemical biology tools for studying host-parasite interactions., Competing Interests: Declaration of interests All authors affiliated with Recursion Pharmaceuticals, Inc have real or potential ownership of public equities in the company and thereby declare a potential conflict., (Copyright © 2023. Published by Elsevier Ltd.)

In vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in Saccharomyces cerevisiae. Sequence analysis identified many genes contributing to the resistance phenotype as well as numerous amino acids in potential targets that may play a role in compound binding. Our work shows that compound-target pairs can be conserved across multiple species. The set of 25 most frequently mutated genes was enriched for transcription factors, and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function SNVs found in a 170 amino acid domain in the two Zn 2 C 6 transcription factors YRR1 and YRM1 (p < 1 × 10 -100 ). This remarkable enrichment for transcription factors as drug resistance genes highlights their important role in the evolution of antifungal xenobiotic resistance and underscores the challenge to develop antifungal treatments that maintain potency., (© 2022. The Author(s).)

The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific laboratories. The aim of MalDA is to improve and accelerate the early antimalarial drug discovery process by identifying new, essential, druggable targets. In addition, it seeks to produce early lead inhibitors that may be advanced into drug candidates suitable for preclinical development and subsequent clinical testing in humans. By sharing resources, including expertise, knowledge, materials, and reagents, the consortium strives to eliminate the structural barriers often encountered in the drug discovery process. Here we discuss the mission of the consortium and its scientific achievements, including the identification of new chemically and biologically validated targets, as well as future scientific directions., Competing Interests: Declaration of Interests K.J.D. holds stock in TropIQ Health Sciences. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Systems glycobiology aims to provide models and analysis tools that account for the biosynthesis, regulation, and interactions with glycoconjugates. To facilitate these methods, there is a need for a clear glycan representation accessible to both computers and humans. Linear Code, a linearized and readily parsable glycan structure representation, is such a language. For this reason, Linear Code was adapted to represent reaction rules, but the syntax has drifted from its original description to accommodate new and originally unforeseen challenges. Here, we delineate the consensuses and inconsistencies that have arisen through this adaptation. We recommend options for a consensus-based extension of Linear Code that can be used for reaction rule specification going forward. Through this extension and specification of Linear Code to reaction rules, we aim to minimize inconsistent symbology thereby making glycan database queries easier. With a clear guide for generating reaction rule descriptions, glycan synthesis models will be more interoperable and reproducible thereby moving glycoinformatics closer to compliance with FAIR standards. Here, we present Linear Code for Reaction Rules (LiCoRR), version 1.0, an unambiguous representation for describing glycosylation reactions in both literature and code., (Copyright © 2020, Kellman et al.; licensee Beilstein-Institut.)

Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of the malaria parasite life cycle. Compounds active against the ABS are then sequentially tested in more difficult assays that predict whether a compound has other beneficial attributes. Although applying this strategy to new chemical libraries may yield new leads, repeated iterations may lead to diminishing returns and the rediscovery of chemotypes hitting well-known targets. Here, we adopted a different strategy to find starting points, testing ∼70,000 open source small molecules from the Global Health Chemical Diversity Library for activity against the liver stage, mature sexual stage, and asexual blood stage malaria parasites in parallel. In addition, instead of using an asexual assay that measures accumulated parasite DNA in the presence of compound (SYBR green), a real time luciferase-dependent parasite viability assay was used that distinguishes slow-acting (delayed death) from fast-acting compounds. Among 382 scaffolds with the activity confirmed by dose response (<10 μM), we discovered 68 novel delayed-death, 84 liver stage, and 68 stage V gametocyte inhibitors as well. Although 89% of the evaluated compounds had activity in only a single life cycle stage, we discovered six potent (half-maximal inhibitory concentration of <1 μM) multistage scaffolds, including a novel cytochrome bc1 chemotype. Our data further show the luciferase-based assays have higher sensitivity. Chemoinformatic analysis of positive and negative compounds identified scaffold families with a strong enrichment for activity against specific or multiple stages.