Biology subjects

Solania, A.

Publications and source records attributed to Solania, A..

3 recordsLinked to original sources

bioRxiv2025

The Secreted Metabolite Isopentenyladenine from Faecalibacterium prausnitzii Mitigates Gut Inflammation

Colonic microbiome dysbiosis is correlated with inflammatory bowel disease (IBD), and depletion of the commensal bacterium Faecalibacterium prausnitzii (F. prausnitzii) is routinely observed in the metagenomic analyses of IBD patient microbiome samples. F. prausnitzii is likely beneficial to hosts, as oral administration of F. prausnitzii strain A2-165 has anti-inflammatory properties in murine models of colitis. Previous studies attribute the anti-inflammatory effects of F. prausnitzii A2-165 to production of the short-chain fatty acid butyrate, as well as a 15 kDa protein known as microbial anti-inflammatory molecule (MAM). Here, we verified that oral dosing of strain A2-165 protects against DSS-induced murine colitis and further show the aqueous-soluble secreted fraction of overnight cultures from a collection of F. prausnitzii strain inhibit inflammatory signatures, including the activation of the hosts NF-{kappa}B pathway, production of IL-8, and differentiation of naive T cells into the TH17 lineage. We find that MAM is secreted in extracellular vesicles; however, MAM-containing vesicles do not have anti-inflammatory properties in our collection of assays and suggests that MAM is likely not a direct contributor. Untargeted and targeted mass spectrometry metabolomics analyses on the soluble anti-inflammatory secretome yielded several unique F. prausnitzii metabolites, including isopentenyladenine. We demonstrated isopentenyladenine independently modulates host cellular signaling and immune responses and suggests this newly identified metabolite with human immunomodulatory properties may be useful towards the discovery of IBD-focused therapeutics.

microbiology↗

bioRxiv2024

Caspase prime-side active-site characterization with non-hydrolyzable peptides assists in the design of a caspase-7-selective irreversible probe.

Limited structural information and biochemical studies are available that demonstrate how the prime side of cysteine protease active sites, such as for human caspases, are used for substrate recognition and how these binding regions can be exploited in the design of inhibitors and probes. Reported small molecules that interact with, and are optimized for, the prime side of caspase active sites are limited to methylketone leaving groups and other nonpeptidic inhibitor moieties, such as aza-Michael acceptors. We present the design, synthesis, and co-complex x-ray structures of the first prime-side elongated non-hydrolyzable peptidomimetic ketomethylene inhibitors designed to interrogate the S4-S4 active-site binding pockets of the executioner caspases-3 and -7. In addition to our structures depicting the first examples of an active-site cysteine in complex with a P1 residue trapped in a non-covalent tetrahedral intermediate, we elucidated prime-side binding interactions for pockets S1 through S4 with our biologically relevant peptide Ac-DEVD-Propionate-AAA. Despite the substantial homology among the caspase active sites, we identified a key difference in the prime-side architecture within binding distance to the P2 inhibitor alanine whereby caspase-3 F128 is substituted for caspase-7 Y151. We exploited this prime-side difference in side chains and their reactivities in the design of non-hydrolyzable ketomethylene-based probes bearing a C-terminal tyrosine-reactive 4-phenyl-1,2,4-triazole-3,5-dione moiety. Our probe selectively labels caspase-7 over caspase-3 and we posit that further characterization of protease active-site prime sides with similar non-hydrolyzable molecules will yield additional tool-like compounds that will assist in establishing the non-redundant roles of caspase family members and other cysteine proteases.

biophysics↗

bioRxiv2019

A selective and rapid cell-permeable inhibitor of human caspase-3

The individual roles and overlapping functionalities the twelve human caspases have during apoptosis and other cellular processes remain poorly resolved primarily due to a lack of chemical tools. Here we present a new selective caspase-3 inhibitor, termed Ac-ATS010-KE, with rapid and irreversible binding kinetics. Relative to previously designed caspase-3-selective molecules that have tremendously abated inhibitory rates and thus limited use in biological settings, the improved kinetics of Ac-ATS010-KE permit its use in a cell-based capacity. We demonstrate that Ac-ATS010-KE prevents apoptosis with comparable efficacy to the general caspase inhibitor Ac-DEVD-KE and surprisingly does so without side-chain methylation. This observation is in contrast to the well-established peptide modification strategy typically employed for improving cellular permeability. Ac-ATS010-KE protects against extrinsic apoptosis, which demonstrates the utility of a thiophene carboxylate leaving group in biological settings, challenges the requisite neutralization of free carboxylic acids to improve cell permeability, and provides a tool-like compound to interrogate the role of caspase-3 in a variety of cellular processes.

biochemistry↗