Research Papers:
Genomewide inhibition of proatherogenic gene expression by multiSTAT targeting compounds as a novel treatment strategy of CVDs
Martyna Plens-Galaska1,*, Malgorzata Szelag1,*, Aida Collado2,4, Patrice Marques3,4, Susana Vallejo5,6, Mariella Ramos-González5,6, Joanna Wesoly2, Maria Jesus Sanz3,4, Concepción Peiró5,6 and Hans A.R. Bluyssen1
1Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
2Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
3Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
4Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
5Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Spain, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
6Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), Madrid, Spain, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
*These authors contributed equally to this work
Correspondence to:
Hans A.R. Bluyssen, email: [email protected]
Keywords: vascular inflammation; STAT; in silico docking; multi-STAT inhibitors; CVDs treatment strategy
Received: August 29, 2017 Accepted: March 29, 2018 Published:
ABSTRACT
Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2 and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs.
Using comparative in silico docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L_F03. This compound targets the SH2 domain of STAT1, STAT2 and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNα. The same in silico and in vitro multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L_F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFNγ and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFNγ+LPS-induced VSMCs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility.
Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDs.