Covant Therapeutics

Thank you Kerry Holtham and Hanson Wade Group for organizing the second Covalent Drug Discovery & Development Summit. On behalf of all my colleagues at Covant Therapeutics, it will be an honor to chair an event with a remarkable panel of subject matter experts from industry and academia. Explore the program here: https://ter.li/bgq1f #drugdiscovery #covalency

A very interesting paper from Prof. Zhibo (Zippo) Liu at Peking University and col., exploring covalent targeted ligation, by means of sulfur (VI) fluoride exchange (SuFEx) chemistry, to enhance radiopharmaceuticals target occupancy and slow down clearance in tumor tissue. The team covalently engineered radiopharmaceuticals to bind to tumor-specific proteins, undergoing tyrosine conjugation through SuFEx reaction. They exemplified their strategy applying it to a fibroblast activation protein (FAP) inhibitor (FAPI), triggering >80% covalent binding to the protein and reducing dissociation for several days. In mice, SuFEx-engineered FAPI showed 257% greater tumor uptake compared to the original FAPI, and increased tumor retention by 13-fold. They observed that uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumor regression in mice. A second SuFEx-engineered covalent radioligand example, targeting prostate-specific membrane antigen (PSMA), also showed enhanced therapeutic efficacy. Overall very exciting combination of radiopharmaceuticals and covalency. #drugdiscovery #oncology #radiotherapy #covalency https://lnkd.in/eNSQKatd

Very nice paper from Monika Raj and her team at Emory University on methionine covalent non-nucleophilic chemical selective labeling. Building on the principle of rapid oxidation, the team reports a Copper(I)-Nitrene Platform (CuNiP) workflow for robust, selective labeling of methionine to generate stable sulfonyl sulfimide conjugates, under physiological conditions, with exemplified minimal cytotoxic effects and dose-dependent labeling. With very interesting insights in Occupied Molecular Orbitals (OMO) stability-reactivity theory (I.e., their analysis revealed that methionine has a lower HOMO-LUMO gap - 5.7 eV - compared to highly nucleophilic amino acid residues such as lysine - 6.4 eV - or cysteine - 6.3 eV) they demonstrate their workflow versatility to label methionine residues in bioactive peptides and proteins, including those in complex cell lysate mixtures, reporting ligandable events across the human proteome. Overall, this method provides additional insights to increase our understanding of the protective role of methionine in diseases associated with elevated levels of reactive oxygen species across modified proteins within different cell compartments (e.g., membrane, cytoplasm, or nucleus), underscoring the platform’s potential in profiling the cellular interactome. #drugdiscovery #proteomics #chemoselectivity #computational https://lnkd.in/epC7XSXi

Great special issue on clinical proteomics. Congratulations Connie Jimenez, Steven Carr, Michael Gillette, and all the contributors. A comprehensive sampler of research and opinion articles by subject matter experts, on technical breakthroughs, challenges, and applications of clinical proteomics. A useful read for scientists and investors to understand the current impact, limitations, and future developments of this burgeoning field. #therapeutics #biomarkers #diagnostics #clinical #translational #proteomics

Tour de force paper from Covant Therapeutics SAB member, Prof. Bernhard Kuster and col. providing one additional example on the impact of mass spectrometry-based proteomics in drug mechanism of action (MoA) elucidation and response biomarker identification. Importantly, the systematic evaluation of drug dose responses on drug-induced proteome expression changes had not been systematically undertaken, limiting insights on the molecular basis of observed drug phenotypic changes. In this paper the team describes a new proteome-wide approach (decryptE) that measures the full dose–response characteristics of drug-induced protein expression changes that informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in more than 1 million dose–response curves that can be interactively explored online in ProteomicsDB and a custom-built Shiny App. Analysis of the collective data provided molecular explanations for known phenotypic drug effects and uncovered new aspects of the MoA of human medicines. For example, the team showed that histone deacetylase inhibitor drugs (HDACi) strongly down-regulated the T cell receptor (TCR) complex and impaired human T cell activation in vitro and ex vivo. This effect offers a rational explanation for the efficacy of histone deacetylase inhibitors in certain lymphomas and autoimmune diseases and explains their poor performance in treating solid tumors. #drugdiscovery #proteomics

Great paper from Jason Gestwicki and col. on expanding the scope of differential scanning fluorimetry (DSF), a biophysical technique that, by means of adding fluorogenic dyes to proteins of interest and applying a thermal ramp, allows to study protein stability, dynamics and protein-ligand interactions. The applicability of DSF had been limited sometimes by incompatibilities between the protein of interest with previously available DSF dyes (e.g., SYPRO-incompatible proteins). The team has developed a protein-adaptive DSF platform (paDSF) that combines a chemically diverse dye library with a streamlined procedure to identify protein–dye pairs on demand. The characteristics of the new dye collection suggest that the paDSF platform may be further generalized and expanded. The new paDSF platform was successfully applied to an impressive 66 out of 70 selected diverse proteins (3x success increase over standard DSF), importantly improving also the breadth of biological processes that were previously out of scope. #drugdiscovery #proteinsciences #biophysics https://lnkd.in/ejFAUyBZ

Great example from Novartis on leveraging several hit finding technologies (e.g., fragment and DNA-encoded libraries, peptides, and virtual screening) to find new binders to different sites on IL1β cytokine that disrupt the interaction with IL1R1 receptor. The team identified IL1β lysine K103 as a target residue suitable for the development of covalent IL-1β/IL1R modulators. #drugdiscovery #covalency

At the core of the development of covalent therapeutics, is the discovery and optimization of the so-called “warhead” attached to the phamacophore. The “warhead” is the reactive group that enables the formation of a (irreversible or reversible) covalent bond with a specific amino acid of the target protein. This reactive moiety drives the rate of inactivation (kinact), the component of the rate of covalent modification (kinact/KI), that is a critical determinant of the ligand reactivity and contributes significantly to proteome-wide selectivity. In this new perspective article, Matthias Gehringer and col. discuss the progress on covalent warheads made in the last five years, and their application in medicinal chemistry and chemical biology. #drugdiscovery #covalency https://lnkd.in/gjxyz_yc

Congratulations to our head of structural proteomics, Dr. Jagat Adhikari, on his latest article from his time in the lab of Prof. Michael L. Gross (Washington University. St. Louis). From a methodological point of view, this work demonstrates that native-MS and Hydrogen-Deuterim Exchange (HDX)-MS done in series provide a valuable approach for protein-ligand (i.e. epitope mapping of antigen–antibody) interactions with peptide-level resolution. Native-MS provides a direct observation of ions with appropriate mass-to-charge (m/z) ratios of binding behavior and sample quality. This does not only save time when performing detailed and time-consuming experiments, such as HDX, but importantly, it also provides guidance for future protein expression and purification. The workflow developed can be applied, beyond epitope mapping, more generally to other systems for which a high-resolution structure of the protein-ligand complex is not available or when higher throughput analytical methods are needed. This last point is important when thinking about the overall impact of the research led by Jagat and his ex-colleagues. At Covant Therapeutics we are excited and convinced (with data to back our sentiments) about the application of combined native MS with structural proteomics techniques (HDX-MS “and beyond”; ask us, we have some cooler methods in our arsenal) for covalent ligand-protein interactions, complementing or bridging the gaps of more traditional methods. #proteomics #structuralbiology #drugdiscovery #targetenablement https://lnkd.in/dbxZJkNQ

Congratulations David Schriemer and team on this publication. Tour de force automating Hydrogen-Deuterium Exchange structural proteomics (HDX-MS) workflow using data-independent acquisition (DIA) analysis. The benefits of time-saving are obvious, add on the possibility to characterize complex samples, including native proteins (e.g. full-length proteins with native post-translational modifications, isolated directly from cells), and this is a game changer. At Covant Therapeutics we rely on structural proteomics to complement crystallography, studying the changes in protein conformation and the temporal dynamics of protein-protein and protein-ligand interactions. These are particularly critical aspects for the development of covalent drugs (where binding kinetics are crucial to potency and selectivity). #structuralbiology #proteomics #covalency