In vitro investigation of integrin-receptor antagonist-induced vascular toxicity in the mouse

Yang

Experimental and Therapeutic Medicine

et al. 2014

Pregnancy is associated with complex immunoreactions. In the present study, the effect of SB-273005, an antagonist of αvβ3 integrin, on the alterations of T helper (Th) cells and their derived cytokines that occur during pregnancy was investigated in mice. Five non-pregnant mice were used as a negative control. Mice were impregnated by co-housing females and males at a ratio of 2:1 overnight and pregnancy was confirmed by the appearance of vaginal plugs the following morning. Day 1 (D1) pregnant mice were randomly divided into two groups (n=20) and were administered either dimethylsulfoxide (mock treatment) or SB-273005 (3 mg/kg) by gavage at D3, D4 and D5. At D8, the levels of Th1 and Th2 cells and interleukin (IL)-2 and IL-10 in the spleen and peripheral blood were determined using flow cytometry and enzyme-linked immunosorbent assay. Pregnancy significantly increased the ratio of Th2:Th1 cells in the spleen compared with that in non-pregnant mice (P<0.01). However, this increase was significantly reduced by SB-273005 (P<0.001). Furthermore, whilst pregnancy decreased Th1 cell-produced IL-2 levels and increased Th2 cell-derived IL-10 levels, SB-273005 reversed both processes (P<0.05 for IL-2; P<0.01 for IL-10). The results from the present study demonstrated that pregnancy induces changes in the spleen, including a reduction of IL-2 and an increase in IL-10 production by Th1 and Th2 cells, respectively, as well as an upregulation of the Th2:Th1 ratio in the spleen. These immunological changes are reversed by SB-273005, indicating an important role for αvβ3 integrin in mediating these immunological alterations.

Section: Introductionmentioning

confidence: 99%

SB-273005, an antagonist of αvβ3 integrin, reduces the production of Th2 cells and cytokine IL-10 in pregnant mice

Yang

Experimental and Therapeutic Medicine

et al. 2014

Ein Instrumentarium von αv‐RGD‐Integrin‐Inhibitoren: Wirkstoffsuche, Herausforderungen und Möglichkeiten

et al. 2018

Es gibt einen Bedarf an wirksamen und sicheren Pharmazeutika für die Behandlung vernachlässigter Krankheiten, und aktuelle Bestrebungen bei der Suche von Inhibitoren des αv‐RGD‐Integrins zielen in diese Richtung. Allerdings erweist sich die Entwicklung von Wirkstoffen im Bereich der αv‐Integrine aufgrund der sehr ähnlichen Strukturen dieser Rezeptoren und der polaren, zwitterionischen Natur des Pharmakophors als notorisch schwierig. Ziel dieses Aufsatzes ist es, einen Leitfaden für die Wirkstoffsuche in diesem Gebiet anzubieten. Wir tun dies, indem wir hier ein Instrumentarium von αv‐Inhibitoren bestehend aus niedermolekularen Verbindungen (“kleinen Molekülen”) und Antikörpern vorstellen. Niedermolekulare αv‐Verbindungen mit erweiterten Profilen in αvβ1‐, αvβ3‐, αvβ5‐, αvβ6‐ und αvβ8‐Zelladhäsionsassays wurden zusammengetragen, um die Auswahl der richtigen Verbindung für das richtige Experiment zu unterstützen. Dies sollte außerdem helfen, die partiellen Selektivitätsprofile von Verbindungen besser zu verstehen, die in unterschiedlichen Assays unterschiedlicher Forschungsinstitute generiert wurden. Die Perspektiven der zukünftigen Forschung an αv‐Integrinen und die zentral wichtige Targetvalidierung werden diskutiert; fundierte Kenntnisse der Selektivität individueller RGD‐αv‐Integrine sind hier ganz entscheidend. Einblicke in das Design niedermolekularer RGD‐Chemotypen für die topische oder orale Verabreichung werden vorgestellt und klinische Befunde zu fortgeschrittenen Molekülen betrachtet.

An αv‐RGD Integrin Inhibitor Toolbox: Drug Discovery Insight, Challenges and Opportunities

et al. 2018

There is a requirement for efficacious and safe medicines to treat diseases with high unmet need. The resurgence in αv-RGD integrin inhibitor drug discovery is poised to contribute to this requirement. However, drug discovery in the αv integrin space is notoriously difficult due to the receptors being structurally very similar as well as the polar zwitterionic nature of the pharmacophore. This Review aims to guide drug discovery research in this field through an αv inhibitor toolbox, consisting of small molecules and antibodies. Small-molecule αv tool compounds with extended profiles in αvβ1, 3, 5, 6 and 8 cell adhesion assays, with key physicochemical properties, have been collated to assist in the selection of the right tool for the right experiment. This should also facilitate an understanding of partial selectivity profiles of compounds generated in different assays across research institutions. Prospects for further αv integrin research and the critical importance of target validation are discussed, where increased knowledge of the selectivity for individual RGD αv integrins is key. Insights into the design of small-molecule RGD chemotypes for topical or oral administration are provided and clinical findings on advanced molecules are examined.