James J. La Clair
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View article: Democratized Discovery of Microsclerodermin F as an Immunophilin Ligand
Democratized Discovery of Microsclerodermin F as an Immunophilin Ligand Open
While immunophilins are well-recognized therapeutic targets, several members of this family of peptidyl-proline isomerases (PPIases) have yet to be subjected to ligand discovery efforts. In this study, we demonstrate a cost-effective means…
View article: Visualizing acyl carrier protein interactions within a crosslinked type I polyketide synthase
Visualizing acyl carrier protein interactions within a crosslinked type I polyketide synthase Open
Using a combination of dual covalent crosslinking and cryo-EM analyses, we elucidate the structure of mycocerosic acid synthase from Mycobacterium tuberculosis trapped in two distinct catalytic states during its iterative cycle. These stru…
View article: Participatory assessment of minor crops: A situated study on hulled wheats
Participatory assessment of minor crops: A situated study on hulled wheats Open
Expanding crop diversity is essential to address the imminent challenges of agriculture. This is especially true for organic farming, which relies on locally adapted species and varieties. Recently, participatory research approaches have e…
View article: Engineering regiospecific methylation of the pladienolides
Engineering regiospecific methylation of the pladienolides Open
Methods were developed to regioselectively methylate pladienolide B to deliver an analogue with reduced metabolic risk and potent activity across a series of tumor cell lines.
View article: Selective Reversal of ADAR1 Splicing Prevents Leukemia Stem Cell Maintenance In Vivo
Selective Reversal of ADAR1 Splicing Prevents Leukemia Stem Cell Maintenance In Vivo Open
Introduction Acute myeloid leukemia (AML) is characterized by a clonal proliferation of myeloid progenitors with a reduced capacity to differentiate into more mature cellular elements. Adenosine deaminase acting on RNA 1 (ADAR1) is an enzy…
View article: Repositioning Brusatol as a Transmission Blocker of Malaria Parasites
Repositioning Brusatol as a Transmission Blocker of Malaria Parasites Open
Currently, primaquine is the only malaria transmission-blocking drug recommended by the WHO. Recent efforts have highlighted the importance of discovering new agents that regulate malarial transmission, with particular interest in agents t…
View article: Cryptic Cerulenin Rearrangement in Ketosynthase Covalent Inhibition
Cryptic Cerulenin Rearrangement in Ketosynthase Covalent Inhibition Open
The antibiotic cerulenin is a fungal natural product identified as a covalent inhibitor of ketosynthases within fatty acid and polyketide biosynthesis. Due to its selective and potent inhibitory activity, cerulenin has found significant ut…
View article: Fluorometric Analysis of Carrier-Protein-Dependent Biosynthesis through a Conformationally Sensitive Solvatochromic Pantetheinamide Probe
Fluorometric Analysis of Carrier-Protein-Dependent Biosynthesis through a Conformationally Sensitive Solvatochromic Pantetheinamide Probe Open
Carrier proteins (CPs) play a fundamental role in the biosynthesis of fatty acids, polyketides, and non-ribosomal peptides, encompassing many medicinally and pharmacologically relevant compounds. Current approaches to analyze novel carrier…
View article: Quantitative Characterization of Chain-Flipping of Acyl Carrier Protein of <i>Escherichia coli</i> Using Chemical Exchange NMR
Quantitative Characterization of Chain-Flipping of Acyl Carrier Protein of <i>Escherichia coli</i> Using Chemical Exchange NMR Open
The acyl carrier protein of Escherichia coli, termed AcpP, is a prototypical example of type II fatty acid synthase systems found in many bacteria. It serves as a central hub by accepting diverse acyl moieties (4-18 carbons) and shuttling …
View article: Visualizing the Interface of Biotin and Fatty Acid Biosynthesis through SuFEx Probes
Visualizing the Interface of Biotin and Fatty Acid Biosynthesis through SuFEx Probes Open
Site-specific covalent conjugation offers a powerful tool to identify and understand protein-protein interactions. In this study, we discover that sulfur fluoride exchange (SuFEx) warheads effectively crosslink the Escherichia coli acyl ca…
View article: Differentiating carrier protein interactions in biosynthetic pathways using dapoxyl solvatochromism
Differentiating carrier protein interactions in biosynthetic pathways using dapoxyl solvatochromism Open
A highly sensitive solvatochromic system was developed to monitor the loading and interactivity of carrier proteins associated with fatty acid, polyketide and non-ribosomal peptide biosynthesis.
View article: Topical delivery of seriniquinone for treatment of skin cancer and fungal infections is enabled by a liquid crystalline lamellar phase
Topical delivery of seriniquinone for treatment of skin cancer and fungal infections is enabled by a liquid crystalline lamellar phase Open
Seriniquinone (SQ) was initially described by our group as an antimelanoma drug candidate and now also as an antifungal drug candidate. Despite its promising in vitro effects, SQ translation has been hindered by poor water-solubility. In t…
View article: Interface Engineering of Carrier-Protein-Dependent Metabolic Pathways
Interface Engineering of Carrier-Protein-Dependent Metabolic Pathways Open
Carrier-protein-dependent metabolic pathways biosynthesize fatty acids, polyketides, and non-ribosomal peptides, producing metabolites with important pharmaceutical, environmental, and industrial properties. Recent findings demonstrate tha…
View article: Nanoscaled Discovery of a Shunt Rifamycin from <i>Salinispora arenicola</i> Using a Three-Color GFP-Tagged <i>Staphylococcus aureus</i> Macrophage Infection Assay
Nanoscaled Discovery of a Shunt Rifamycin from <i>Salinispora arenicola</i> Using a Three-Color GFP-Tagged <i>Staphylococcus aureus</i> Macrophage Infection Assay Open
Antimicrobial resistance has emerged as a global public health threat, and development of novel therapeutics for treating infections caused by multi-drug resistant bacteria is urgent. Staphylococcus aureus is a major human and animal patho…
View article: Stereochemical Control of Splice Modulation in FD-895 Analogues
Stereochemical Control of Splice Modulation in FD-895 Analogues Open
Highly functionalized skeletons of macrolide natural products gain access to rare spatial arrangements of atoms, where changes in stereochemistry can have a profound impact on the structure and function. Spliceosome modulators present a un…
View article: A Survey of Didemnin Depsipeptide Production in Tistrella
A Survey of Didemnin Depsipeptide Production in Tistrella Open
As one of the first families of marine natural products to undergo clinical trials, the didemnin depsipeptides have played a significant role in inspiring the discovery of marine drugs. Originally developed as anticancer therapeutics, the …
View article: Masked cerulenin enables a dual-site selective protein crosslink
Masked cerulenin enables a dual-site selective protein crosslink Open
Translation of the natural product cerulenin into probe for fluorescent labeling and masked crosslinker to evaluate protein–protein interactivity.
View article: Preclinical Development of Seriniquinones as Selective Dermcidin Modulators for the Treatment of Melanoma
Preclinical Development of Seriniquinones as Selective Dermcidin Modulators for the Treatment of Melanoma Open
The bioactive natural product seriniquinone was discovered as a potential melanoma drug, which was produced by the as-yet-undescribed marine bacterium of the rare genus Serinicoccus. As part of a long-term research program aimed at the dis…
View article: Modulation of RNA splicing associated with Wnt signaling pathway using FD-895 and pladienolide B
Modulation of RNA splicing associated with Wnt signaling pathway using FD-895 and pladienolide B Open
Alterations in RNA splicing are associated with different malignancies, including leukemia, lymphoma, and solid tumors. The RNA splicing modulators such as FD-895 and pladienolide B have been investigated in different malignancies to targe…
View article: Three-component assembly of stabilized fluorescent isoindoles
Three-component assembly of stabilized fluorescent isoindoles Open
The tandem addition of an amine and a thiol to an aromatic dialdehyde engages a selective three-component assembly of a stabilized fluorescent isoindole.
View article: Accessing Nystatin through Mariculture
Accessing Nystatin through Mariculture Open
Understanding our oceans and their marine ecosystems has enabled the development of sustainable systems for mariculture. While the bulk of studies to date have focused on the production of food, its remarkable expanse has inspired the tran…
View article: Seriniquinones as Therapeutic Leads for Treatment of BRAF and NRAS Mutant Melanomas
Seriniquinones as Therapeutic Leads for Treatment of BRAF and NRAS Mutant Melanomas Open
Isolated from the marine bacteria Serinicoccus sp., seriniquinone (SQ1) has been characterized by its selective activity in melanoma cell lines marked by its modulation of human dermcidin and induction of autophagy and apoptosis. While an …
View article: FD-895 and Pladienolide B Modulate RNA Splicing Associated With Wnt Signaling Pathway
FD-895 and Pladienolide B Modulate RNA Splicing Associated With Wnt Signaling Pathway Open
BackgroundAlterations in RNA splicing are associated with different malignancies including leukemia, lymphoma, and solid tumors. The RNA splicing modulators such as FD-895 and pladienolide B have been investigated in different malignancies…
View article: Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras
Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras Open
A current bottleneck in the development of proteolysis targeting chimeras (PROTACs) is the empirical nature of linker length structure-activity relationships (SARs). A multidisciplinary approach to alleviate the bottleneck is detailed here…
View article: Lessons in Organic Fluorescent Probe Discovery
Lessons in Organic Fluorescent Probe Discovery Open
Fluorescent probes have gained profound use in biotechnology, drug discovery, medical diagnostics, molecular and cell biology. The development of methods for the translation of fluorophores into fluorescent probes continues to be a robust …
View article: Synthase-Selective Exploration of a Tunicate Microbiome by Activity-Guided Single-Cell Genomics
Synthase-Selective Exploration of a Tunicate Microbiome by Activity-Guided Single-Cell Genomics Open
While thousands of environmental metagenomes have been mined for the presence of novel biosynthetic gene clusters, such computational predictions do not provide evidence of their in vivo biosynthetic functionality. Using fluorescent in sit…