Author: Supuran, Claudiu T. ; Michelet, Bastien ; Nocentini, Alessio ; Bartolucci, Gianluca ; Martin-Mingot, Agnès ; Berrino, Emanuela ; Gratteri, Paola ; Carta, Fabrizio ; Vitse, Kassandra ; Thibaudeau, Sébastien

Carbonic anhydrase (CA) IV is a membrane-bound enzyme involved in important physio-pathological processes, such as excitation-contraction coupling in heart muscle, central nervous system (CNS) extracellular buffering, and mediation of inflammatory response after stroke. Known since the mid-1980s, this isoform is still largely unexplored when compared to other isoforms, mostly for the current lack of inhibitors targeting selectively this isoform. The discovery of selective CA IV inhibitors is thus largely awaited. In this work, we report β-(di) fluoropropyl diamines as effective CA IV inhibitors, opening real perspectives for a new mode of selective inhibition of this isoform. Inhibition data reveal that the essential structure core to ensure a potent and selective inhibition of CA IV is the N-propyldiamine. Molecular modeling studies were employed to understand the binding mode of the synthesized amines. Conformational searches within the active site space carried out in an implicit solvent (water) model were also conducted.

01 Mar 2021·Journal of Molecular and Cellular CardiologyQ2 · MEDICINE

Inhibition of endoplasmic reticulum stress mediates the ameliorative effect of apelin on vascular calcification

Q2 · MEDICINE

Article

Author: Liu, Chenxi ; Geng, Haigang ; Hao, Wei ; Yang, Rui ; Wu, Yuming ; Li, Ying ; Teng, Xu ; Jin, Sheng ; Li, Yuqing ; Yang, Ziyuan ; Wang, Xiaoning ; Li, Yanqing

AIMSApelin is the endogenous ligand of G protein-coupled receptor APJ and play an important role in the regulation of cardiovascular homeostasis. We aimed to investigate whether apelin ameliorates vascular calcification (VC) by inhibition of endoplasmic reticulum stress (ERS).METHODS AND RESULTSVC model in rats was induced by nicotine plus vitamin D, while calcification of vascular smooth muscle cell (VSMC) was induced by beta-glycerophosphate. Alizarin Red S staining showed dramatic calcium deposition in the aorta of rats with VC, while calcium contents and ALP activity also increased in calcified aorta. Protein levels of apelin and APJ were decreased in the calcified aorta. In rats with VC, apelin treatment significantly ameliorated aortic calcification, compliance and stimulation of ERS. The ameliorative effect of apelin on VC and ERS was also observed in calcified VSMCs. ERS stimulator (tunicamycin or DTT) blocked the beneficial effect of apelin. Apelin treatment activated the PI3K/Akt signaling, blockage of which by wortmannin or inhibitor IV prevented the ameliorative effect of apelin, while ERS inhibitor 4-PBA rescued the blockade effect of wortmannin. Akt-induced GSK inhibition prevented the phosphorylation of PERK and IRE1, and the activation of these two major ERS branches. F13A blocked the ameliorative effect of apelin on VC and ERS, which was reversed by treatment with 4-PBA or Akt activator SC79 CONCLUSIONS: Apelin ameliorated VC by binding to APJ and then prevented ERS activation by stimulating Akt signaling. These results might provide new target for therapy and prevention of VC.

03 Apr 2020·ChemMedChem

Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development

Article

Author: Tse‐Dinh, Yuk‐Ching ; Chapagain, Prem P. ; Seddek, Ahmed ; Tiwari, Purushottam B. ; Annamalai, Thirunavukkarasu ; Üren, Aykut

AbstractA topoisomerase‐DNA transient covalent complex can be a druggable target for novel topoisomerase poison inhibitors that represent a new class of antibacterial or anticancer drugs. Herein, we have investigated molecular features of the functionally important Escherichia coli topoisomerase I (EctopoI)‐DNA covalent complex (EctopoIcc) for molecular simulations, which is very useful in the development of new antibacterial drugs. To demonstrate the usefulness of our approach, we used a model small molecule (SM), NSC76027, obtained from virtual screening. We examined the direct binding of NSC76027 to EctopoI as well as inhibition of EctopoI relaxation activity of this SM via experimental techniques. We then performed molecular dynamics (MD) simulations to investigate the dynamics and stability of EctopoIcc and EctopoI‐NSC76027‐DNA ternary complex. Our simulation results show that NSC76027 forms a stable ternary complex with EctopoIcc. EctopoI investigated here also serves as a model system for investigating a complex of topoisomerase and DNA in which DNA is covalently attached to the protein.

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Preclinical	JP	Dainippon Pharmaceutical Co., Ltd.	05 Jun 2004

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