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...

NIH Funding Opportunities and Notices in the NIH Guide for Grants and Contracts: New Application Structure for NIH-Funded International Collaborations NOT-OD-25-155. NIH

Francis Collins, MD, PhD, lauds lifesaving research supported by the National Institutes of Health, explains why he left, and warns of scientific brain drain.

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

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Carbohydrates are ubiquitous biomolecules that play indispensable roles in living systems, functioning in cellular communication, genetic information storage, cellular energy provision, structural ...

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.

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.

Research Fellow in Animal Protozoology (Fixed Term - 5 years) in the Department of Pathology at the University of Cambridge.

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of...

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.

Pancreatic cancer (PC) is a deadly cancer with a high mortality rate. The unique characteristics of PC, including desmoplasia and immunosuppression, h…

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.

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...

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,...

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....

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 ...

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....