Biology subjects

Hassanzadeh, M.

Publications and source records attributed to Hassanzadeh, M..

3 recordsLinked to original sources

bioRxiv2025

Arylsulfatase I is a novel lysosomal chondroitin sulfatase regulating endochondral ossification

During endochondral ossification, chondrocytes undergo maturation and biochemically modify the collagenous extracellular matrix of cartilage. Similar modifications to cartilage proteoglycans (PGs), which are predominantly chondroitin sulfate, have not been characterized. Using synchrotron X-ray fluorescence imaging, we demonstrated that PG sulfation significantly decreased during cartilage maturation of chick embryos. Laser-capture microdissection and RNAseq revealed upregulation of Arylsulfatase I (Arsi) in mature cartilage of mouse. ARSI protein also increased in mature cartilage of mouse and chick in vivo and during maturation of ATDC5 chondrocytes in vitro, whereas expression of the two known chondroitin sulfate PG sulfatases (ARSB and GALNS) was not specific to mature cartilage. Colocalization studies suggested that ARSI is lysosomal, and functional assays revealed that ARSI impacts lysosome homeostasis in chondrocytes. Biochemical analyses of ARSI gain and loss of function cell lines and isolated cell-free systems revealed that ARSI is a novel chondroitin sulfatase, specifically desulfating GalNAc4S at the nonreducing terminal of CS/DS. Finally, Arsi knockout in RCS chondrocytes caused increased expression of maturation genes, such as Col10a1 and Mmp13. In total, these data identify ARSI as a novel PG sulfatase regulating endochondral ossification.

cell biology↗

bioRxiv2025

Tunable Bias Signaling of the Angiotensin II Type 1 Receptor for Inotropy via C-Terminal Peptide Modifications and Allosteric Site Targeting

The angiotensin II (AngII) type 1 receptor (AT1R) is a key prototypical G protein-coupled receptor in cardiovascular regulation. Biased agonists that activate G protein or {beta}-arrestin pathways provide promising therapeutic potential, but the molecular determinants for this signaling bias and its physiological implications remain poorly understood. This study profiles AngII analogs with modifications at the C-terminal Phe8, revealing that analogs 11, 12, and 29a exhibit varying degrees of Gq engagement while maintaining potent {beta}-arrestin recruitment. Notably, 12 enhances left ventricular ejection fraction with minimal pressor responses in normotensive rats, while other analogs with variable Gq activity do not promote inotropy. Molecular modeling indicates that the unique profile of 12 results from its flexible long side chain engaging a deep allosteric pocket within AT1R. This study demonstrates that engineering AngIIs C-terminus enables selective tuning of AT1R signaling to control arterial versus cardiac responses, providing strategies for developing improved cardiovascular therapeutics. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/670122v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@52b49corg.highwire.dtl.DTLVardef@1cf92dcorg.highwire.dtl.DTLVardef@b2c103org.highwire.dtl.DTLVardef@19db799_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency

TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and in cell entry of respiratory viruses. To date, no inhibitors have been specifically developed toward this protease. In this study, a chemical library of 65 ketobenzothiazole-based peptidomimetic molecules was screened against a proteolytically active form of recombinant TMPRSS13 to identify novel inhibitors. Following an initial round of screening, subsequent synthesis of additional derivatives supported by molecular modelling, uncovered important molecular determinants involved in TMPRSS13 inhibition. One inhibitor, N-0430, achieved low nanomolar affinity towards TMPRSS13 activity in a cellular context. Using a SARS-CoV-2 pseudovirus cell entry model, we further show the ability of N-0430 to block TMPRSS13-dependent entry of the pseudovirus. The identified peptidomimetic inhibitors and the molecular insights of their potency gained from this study will aid in the development of specific TMPRSS13 inhibitors.

pharmacology and toxicology↗