Biology subjects

Fath, M.

Publications and source records attributed to Fath, M..

3 recordsLinked to original sources

bioRxiv2025

Inhibitors of membrane associated serine proteases block replication of coronavirus SARS-CoV-2 and influenza virus H1N1

TMPRSS2 is a membrane associated serine protease which is important in the viral pathogenesis of coronaviruses and influenza viruses. We developed mechanism-based covalent -ketobenzothiazole (kbt) inhibitors using substrate specificity PS-SCL screening of TMPRSS2 as a rational guide for inhibitor design. Three distinct focused libraries of tetrapeptide kbts were synthesized and evaluated for their inhibition of TMPRSS2, matriptase and other serine proteases. We also investigated different capping groups for the previously reported tripeptide inhibitor Ac-QFR-kbt (MM3144) to increase its selectivity over the blood coagulation protease factor Xa. The most potent compounds were tested for their ability to inhibit viral replication of SARS-CoV-2 coronavirus and the H1N1 influenza virus. The most active compounds were profiled for their pharmacokinetics (PK) in mice. Several promising new compounds were identified with improved potency, selectivity, and drug-like properties including Bz-QFR-kbt (CA1043) and Cbz-QFR-kbt (ZFH9141) with an IC50 of 150 nM and 60 nM for H1N1, respectively.

microbiology↗

bioRxiv2023

Auranofin Inhibition of Thioredoxin Reductase in a Preclinical Model of Small Cell Lung Cancer

Thioredoxin Reductase (TrxR) is a key enzyme in hydroperoxide detoxification through peroxiredoxin enzymes and in thiol-mediated redox regulation of cell signaling. Because cancer cells produce increased steady-state levels of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide), TrxR is currently being targeted in clinical trials using the anti-rheumatic drug, auranofin (AF). AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the lung atypical (neuroendocrine tumor) NET cell line H727. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, a multi-kinase inhibitor that was shown to decrease intracellular glutathione. The pharmacokinetic and pharmacodynamic properties of AF treatment in a mouse SCLC xenograft model was examined to maximize inhibition of TrxR activity without causing toxicity. AF was administered intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1 to 5 days in mice with DMS273 xenografts. Plasma levels of AF were 10-20 M (determined by mass spectrometry of gold) and the optimal inhibition of TrxR (50 %) was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. When this daily AF treatment was extended for 14 days a significant prolongation of median survival from 19 to 23 days (p=0.04, N=30 controls, 28 AF) was observed without causing changes in animal bodyweight, CBCs, bone marrow toxicity, blood urea nitrogen, or creatinine. These results show that AF is an effective inhibitor of TrxR both in vitro and in vivo in SCLC, capable of sensitizing NETs and SCLC to sorafenib, and supports the hypothesis that AF could be used as an adjuvant therapy with agents known to induce disruptions in thiol metabolism to enhance therapeutic efficacy.

cancer biology↗

bioRxiv2020

A Wnt-specific astacin proteinase controls head formation in Hydra

The Hydra head organizer acts as a signaling center that initiates and maintains the primary body axis in steady state polyps and during budding or regeneration. Wnt/beta-Catenin signaling functions as a primary cue controlling this process, but how Wnt ligand activity is locally restricted at the protein level is poorly understood. Here we report the identification of an astacin family proteinase as a Wnt processing factor. Hydra astacin-7 (HAS-7) is expressed from gland cells as an apical-distal gradient in the body column, peaking close beneath the tentacle zone. HAS-7 siRNA knockdown abrogates HyWnt3 proteolysis in the head tissue and induces a robust double axis phenotype, which is rescued by simultaneous HyWnt3 knockdown. Accordingly, double axes are also observed in conditions of increased Wnt levels as in transgenic actin::HyWnt3 and HyDkk1/2/4 siRNA treated animals. HyWnt3-induced double axes in Xenopus embryos could be rescued by co-injection of HAS-7 mRNA. Mathematical modelling combined with experimental promotor analysis indicate an indirect regulation of HAS-7 by beta-Catenin, expanding the classical Turing-type activator-inhibitor model. Our data suggest a negative regulatory function of Wnt processing astacin proteinases in the global patterning of the oral-aboral axis in Hydra.

developmental biology↗