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A New Class of Kinase Inhibitors for the Treatment of Cardiovascular Disease

Experimental Biology and Medicine

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Experimental Biology and Medicine

Aug 12, 2019, 07:00 ET

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WASHINGTON, Aug. 12, 2019 /PRNewswire/ -- An article published in Experimental Biology and Medicine (Volume 244, Issue 11, August, 2019) (https://journals.sagepub.com/doi/pdf/10.1177/1535370219849581) describes a new class of kinase inhibitors. The study, led by Dr. Robert Schwartz in the Department of Biology and Biochemistry at the University of Houston and The Texas Heart Institute at the Texas Medical Center in Houston, Texas (USA), reports that peptide inhibitors targeting a unique site on a kinase molecule facilitate vascular relaxation.

Cardiovascular disease is the leading cause of mortality in western civilization. High blood pressure, or hypertension, is the principal cause of cardiovascular disease and afflicts 1 out of every 3 adults. Hypertension is regulated in large part by smooth muscle cells in the arteries. Contraction of vascular smooth muscle cells creates resistance to the forces generated by blood flow and allows arteries to maintain their shape. Rho-activated kinases (ROCKs) are important signaling components in smooth muscle cells, and attenuation of ROCK signaling reduces disease progression in many pre-clinical models of cardiovascular disease. However, specificity is a major challenge in developing inhibitors that target ROCKs. Many small molecule therapeutics target the ATP binding site and have significant side effects because this region is highly conserved among all kinases throughout the body. One strategy for increasing specificity is developing inhibitors that target divergent regulatory domains of the kinase instead of the highly conserved ATP-binding site.

In the current study, Dr. Schwartz and colleagues used novel phage display techniques to identify peptides that bind to the ROCK catalytic domain. One peptide inhibited ROCK activity in biochemical and cell-based assays. Alanine scanning mutagenesis was used to generate an optimized lead that facilitated vascular relaxation. Dr. Schwartz said "our studies will open new avenues for drug discovery and specificity by targeting regions of the kinase that are significantly different between the proteins, the activation loop." Dr. Warren Zimmer, senior member of the research group, stated that "these studies represent a game-changer for targeted therapies, not only for hypertension, but for many diseases where enzymes such as kinases are important components of disease progression."

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology & Medicine, said "Schwartz and colleagues have identified polypeptides that can inhibit Rho-activated kinases (ROCKs) by binding to the catalytic domain while not competing with ATP binding sites. These ROCK inhibitors represent potential therapeutics for multiple disorders including hypertension and cardiovascular diseases."

Experimental Biology and Medicine is a global journal dedicated to the publication of multidisciplinary and interdisciplinary research in the biomedical sciences. The journal was first established in 1903. Experimental Biology and Medicine is the journal of the Society of Experimental Biology and Medicine. To learn about the benefits of society membership, visit www.sebm.org. If interested in publishing in the journal, please visit http://ebm.sagepub.com.

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