Jim Janetka

Profiling the proteome-wide selectivity of diverse electrophiles - Nature Chemistry Covalent inhibitors are powerful entities in drug discovery. Now the amino acid selectivity and reactivity of a diverse electrophile library have been assessed proteome-wide using an unbiased workflow...

How can we study target engagement and selectivity of covalent inhibitors? Which electrophilic probes are best suited to study a certain amino acid?

Our study on "Profiling the proteome-wide selectivity of diverse electrophiles" is published in Nature Chemistry.(1/7)

www.nature.com/articles/s41...

Submit your research to JCM's Special Series, "Diagnostic Testing for Mycobacteria."

Tuberculosis (TB) remains one of the world’s leading infectious killers, and NTM infections are rising. #JClinMicro invites submissions to our "Diagnostic Testing for Mycobacteria" series. 📄 Share your research now → asm.social/2B6

New NIH Notice about International Collaborations

grants.nih.gov/grants/guide...

1/3

Oooh. Interesting.

“Click Chemistry Methodology: The Novel Paintbrush of Drug Design”, a Review published in ACS Chemical Biology

Check out this Review, published in ACS Chemical Biology: “Click Chemistry Methodology: The Novel Paintbrush of Drug Design”.

Find out more: buff.ly/reGfX7R

What an unprecedented and strong bipartisan voice to sound this alarm. Will the Republican Congress wake up and stop playing politics with the health of the American people?

Former NIH chief calls research cuts “careless” and “heartless” Francis Collins, MD, PhD, lauds lifesaving research supported by the National Institutes of Health, explains why he left, and warns of scientific brain drain.

Was the Ginther finding of award bias against Black PIs a mistake that was self-corrected on your watch, Francis?

www.aamc.org/news/former-...

Drug screens using the nematode Caenorhabditis elegans Abstract. Since its inception as a model system, Caenorhabditis elegans has provided insight about the mechanism of action of drugs through genetic analyse

'Why would anyone want to screen drugs against the model nematode Caenorhabditis elegans? (...) This review aims to provide insight and perspective into this question.'

Sign the IMPEACH RFK Citizens' Petition to Congress — STAND UP FOR SCIENCE Join with us to sign our Citizens' Petition to the US Congress to choose the people over Trump and Impeach RFK Jr Now!

www.standupforscience.net/rfk-impeachm...
IMPEACH AND REMOVE RFK JR. SIGN HERE. SHARE WITH EVERYONE YOU KNOW.

Recent advances in the development of promising carbohydrate-based therapeutics Carbohydrates are ubiquitous biomolecules that play indispensable roles in living systems, functioning in cellular communication, genetic information storage, cellular energy provision, structural ...

Recent advances in the development of promising carbohydrate-based therapeutics

doi.org/10.1080/1746...

Structure‐Based Drug Design of Novel Heterocyclic Scaffolds as TgCDPK1 Inhibitors A) Structures and biological activity of 44 pyrazolopyrimidine, CZ29 pyrrolopyrimidine, and 3 quinoline Amide TgCDPK1 inhibitors; B) Compounds 44, CZ29 (analog), and 3 bound to TgCDPK1.

Structure‐Based Drug Design of Novel Heterocyclic Scaffolds as TgCDPK1 Inhibitors - Kooner - ChemMedChem - Wiley Online Library chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/...

Direct Cellular Screening of Pd-Mediated Arylation of Cyclic Peptide Binders Targeting Ubiquitin Chains: Toward Modulating NEMO Liquid–Liquid Phase Separation Ubiquitination is a critical post-translational modification that regulates key cellular processes such as protein degradation and DNA damage repair. Targeting a specific type of ubiquitin chain (e.g., Lys48 or Lys63-linked ubiquitin chain) via cyclic peptides presents a new strategy to modulate biological processes with therapeutic potential for various diseases. However, such a strategy remains challenging due to the obstacles of cell permeability and bioactivity. Here, we present a new method that directly assesses these parameters by integrating palladium-mediated Cys arylation with direct cellular screening. Using CP4, a previously identified cyclic peptide modulator of Lys63-linked ubiquitin chains, we generated a focused library of arylated analogues and optimized the Pd-mediated arylation for direct cellular screening. We discovered a new analog, CP-P12-ArH, that demonstrated enhanced binding affinity and robust bioactivity, as evidenced by increased γ-H2AX phosphorylation and apoptosis induction in cancer cells. Furthermore, CP-P12-ArH effectively inhibited the in vitro formation of NF-κB essential modulator (NEMO) biomolecular condensates by disrupting the elongation of Lys63-linked ubiquitin chains, offering a novel way to modulate NF-κB signaling. This work establishes a generalizable platform for the rapid optimization of cyclic peptide therapeutics targeting protein–protein interactions.

Interesting paper by the group of Ashraf Brik in @jacs.acspublications.org. Pd-mediated modification of cyclic peptides allows to combinatorially generate S-arylated derivatives and directly screen them for activity in cells.

pubs.acs.org/doi/10....
#ChemSky #ChemBio #DirectToBiology #D2B

If you are interested in peptide-based protein binders, check out this new @biorxivpreprint.bsky.social by the group of @sebastianpomplun.bsky.social of our @led3hub.bsky.social on their computer-based design.

An exciting opportunity to start an independent position as a research fellow in protozoan parasitology at Christ's College, Cambridge and the Department of Pathology:
www.jobs.cam.ac.uk/job/52020/

Novel approaches to glycomimetic design: development of small molecular weight lectin antagonists: Expert Opinion on Drug Discovery: Vol 16, No 5 www.tandfonline.com/doi/abs/10.1...

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells | PNAS The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of...

A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells | PNAS www.pnas.org/doi/full/10....

Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression Hepatocyte growth factor (HGF), the ligand for the MET receptor tyrosine kinase, is a tumor-promoting factor that is abundant in the tumor microenvironment. Proteolytic activation of inactive pro-HGF by one or more of the serine endopeptidases matriptase, hepsin, and HGF activator is the rate-limiting step in HGF/MET signaling. Herein, we have rationally designed a novel class of side chain cyclized macrocyclic peptide inhibitors. The new series of cyclic tripeptides has superior metabolic stability and significantly improved pharmacokinetics in mice relative to the corresponding linear peptides. We identified the lead compound VD2173 that potently inhibits matriptase and hepsin, which was tested in parallel alongside the acyclic inhibitor ZFH7116 using both in vitro and in vivo models of lung cancer. We demonstrated that both compounds block pro-HGF activation, abrogate HGF-mediated wound healing, and overcome resistance to EGFR- and MET-targeted therapy in lung cancer models. Furthermore, VD2173 inhibited HGF-dependent growth of lung cancer tumors in mice.

Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression | Journal of Medicinal Chemistry pubs.acs.org/doi/abs/10.1...

www.mdpi.com/2076-0817/11...
Aspartyl Protease Inhibitors as Anti-Filarial Drugs

HGF/c-Met pathway inhibition combined with chemotherapy increases cytotoxic T-cell infiltration and inhibits pancreatic tumour growth and metastasis Pancreatic cancer (PC) is a deadly cancer with a high mortality rate. The unique characteristics of PC, including desmoplasia and immunosuppression, h…

www.sciencedirect.com/science/arti...

Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections FmlH, a bacterial adhesin of uropathogenic Escherichia coli (UPEC), has been shown to provide a fitness advantage in colonizing the bladder during chronic urinary tract infections (UTIs). Previously reported ortho-biphenyl glycosides based on βGal and βGalNAc have excellent binding affinity to FmlH and potently block binding to its natural carbohydrate receptor, but they lack oral bioavailability. In this paper, we outline studies where we have optimized compounds for improved pharmacokinetics, leading to the discovery of novel analogues with good oral bioavailability. We synthesized galactosides with the anomeric O-linker replaced with more stable S- and C-linked linkers. We also investigated modifications to the GalNAc sugar and modifications to the biphenyl aglycone. We identified GalNAc 69 with an IC50 of 0.19 μM against FmlH and 53% oral bioavailability in mice. We also obtained a FimlH-bound X-ray structure of lead compound 69 (AM4085) which has potential as a new antivirulence therapeutic for UTIs.

Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections | Journal of Medicinal Chemistry pubs.acs.org/doi/abs/10.1...

FEBS Press Serine protease hepsin, which is commonly overexpressed in prostate, ovarian, and breast cancers, promotes cancer progression with yet unclear mechanisms. We show with breast cancer patient-derived e...

Hepsin promotes breast tumor growth signaling via the TGFβ‐EGFR axis - Belitškin - 2024 - Molecular Oncology - Wiley Online Library febs.onlinelibrary.wiley.com/doi/full/10....

Mechanism-Based Macrocyclic Inhibitors of Serine Proteases Protease inhibitor drug discovery is challenged by the lack of cellular and oral permeability, selectivity, metabolic stability, and rapid clearance of peptides. Here, we describe the rational design,...

Mechanism-Based Macrocyclic Inhibitors of Serine Proteases | Journal of Medicinal Chemistry pubs.acs.org/doi/abs/10.1...

Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein‐Protein Interaction We have discovered a new chemical series of small molecules which block the protein-protein interaction of ERCC1 and XPA, which are important in DNA damage repair and resistance to chemotherapy. We f....

Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein‐Protein Interaction - Obermann - 2024 - ChemMedChem - Wiley Online Library chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1...

Efficacy of host cell serine protease inhibitor MM3122 against SARS-CoV-2 for treatment and prevention of COVID-19 | Journal of Virology SARS-CoV-2 and other emerging RNA coronaviruses are a present and future threat in causing widespread endemic and pandemic infection and disease. In this paper, we have shown that the novel host cell ...

Efficacy of host cell serine protease inhibitor MM3122 against SARS-CoV-2 for treatment and prevention of COVID-19 | Journal of Virology journals.asm.org/doi/full/10....

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin Inhibition of the proteolytic processing of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for the drug discovery of novel anticancer therapeutics w....

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin - Mahoney - 2024 - Protein Science - Wiley Online Library onlinelibrary.wiley.com/doi/abs/10.1...

Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer - Cellular and Molecular Life Sciences Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate lig...

link.springer.com/article/10.1...

@scotthultgren.bsky.social

Conformational ensembles in Klebsiella pneumoniae FimH impact uropathogenesis | PNAS Klebsiella pneumoniae is an important pathogen causing difficult-to-treat urinary tract infections (UTIs). Over 1.5 million women per year suffer f...

A recent paper with collaborators

www.pnas.org/doi/10.1073/...

Discovery of Human PIM Kinase Inhibitors as a Class of Anthelmintic Drugs to Treat Intestinal Nematode Infections Soil-transmitted helminth (STH) infections affect one-fourth of the global population and pose a significant threat to human and animal health, with limited treatment options and emerging drug resista...

We have another two coming out very soon!

Discovery of Human PIM Kinase Inhibitors as a Class of Anthelmintic Drugs to Treat Intestinal Nematode Infections | ACS Infectious Diseases pubs.acs.org/doi/abs/10.1...

Macrocyclic Phage Display for Identification of Selective Protease Substrates Traditional methods for identifying selective protease substrates have primarily relied on synthetic libraries of linear peptides, which offer limited sequence and structural diversity. Here, we present an approach that leverages phage display technology to screen large libraries of chemically modified cyclic peptides, enabling the identification of highly selective substrates for a protease of interest. Our method uses a reactive chemical linker to cyclize peptides on the phage surface, while simultaneously incorporating an affinity tag and a fluorescent reporter. The affinity tag enables capture of the phage library and subsequent release of phages expressing optimal substrates upon incubation with a protease of interest. The addition of a turn-on fluorescent reporter allows direct quantification of cleavage efficiency throughout each selection round. The resulting identified substrates can then be chemically synthesized, optimized and validated using recombinant enzymes and cells. We demonstrate the utility of this approach using Fibroblast Activation Protein α (FAPα) and the related proline-specific protease, dipeptidyl peptidase-4 (DPP4), as targets. Phage selection and subsequent optimization identified substrates with selectivity for each target that have the potential to serve as valuable tools for applications in basic biology and fluorescence image-guided surgery (FIGS). Overall, our strategy provides a rapid and unbiased platform for effectively discovering highly selective, non-natural protease substrates, overcoming key limitations of existing methods.

Macrocyclic Phage Display for Identification of Selective Protease Substrates | Journal of the American Chemical Society pubs.acs.org/doi/full/10....