Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Studies Suggest New Key to “Switching Off” Hypertension

23.07.2013
A team of University of California, San Diego researchers has designed new compounds that mimic those naturally used by the body to regulate blood pressure. The most promising of them may literally be the key to controlling hypertension, switching off the signaling pathways that lead to the deadly condition.

Catestatin-mimic pharmacophore model. Pharmacophore centers correspond to hydrophobic residues Leu5, Phe7, and Phe14; and positively charged residues Arg8, Arg10, and Arg15. Green circles represent hydrophobes and aromatic/hydrophobic features, while dark-blue circles represent NCN+ groups/cations/H-bond donors. Ribbon diagram and three-dimensional residue structures belong to superimposed catestatin. Image courtesy of Valentina Kouznetsova, UC San Diego.

Published online this month in Bioorganic & Medicinal Chemistry, the scientists studied the properties of the peptide called catestatin that binds nicotinic acetylcholine receptors found in the nervous system, and developed a pharmacophore model of its active centers.

They next screened a library of compounds for molecules that might match this 3D “fingerprint”. The scientists then took their in-silico findings and applied them to lab experiments, uncovering compounds that successfully lowered hypertension.

“This approach demonstrates the effectiveness of rational design of novel drug candidates,” said lead author Igor F. Tsigelny, a research scientist with the university’s San Diego Supercomputer Center (SDSC), as well as the UC San Diego Moores Cancer Center and the Department of Neurosciences.

“Our results suggest that analogs can be designed to match the action of catestatin, which the body uses to regulate blood pressure,” said Daniel T. O’Connor, a professor at the UC San Diego School of Medicine and senior author of the study. “Those designer analogs could ultimately be used for treatment of hypertension or autonomic dysfunction.”

The research may lead to a new class of treatments for hypertension, a disease which affects about 76 million people, or about one in three adults, in the United States, according to the American Heart Association. Untreated, it damages the blood vessels and is a leading risk factor for kidney failure, heart attack, and stroke.

Despite being a common and lethal cardiovascular risk factor, hypertension remains only partially controlled by current antihypertensive medications, most of which have serious side effects. Specifically, the SDSC/UC San Diego researchers targeted the hormone catestatin for therapeutic potential. Catestatin acts as the gatekeeper for the secretion of catecholamines – hormones that are released into the blood during times of physical or emotional stress. A drug that mimics the action of catestatin would thus allow people to control the hormones that regulate blood pressure.

Based on earlier studies of the structure of catestatin, O’Connor, Tsigelny, and their colleagues figured out which residues of catestatin are responsible for binding to the nicotinic receptor – similar to mapping how the ridges on a key fit into a lock. They created a three-dimensional model of the most important binding centers – the pharmacophore model. Then they screened about 250,000 3D compound structures in the Open NCI Database to select ones that fit this fingerprint of active centers. They discovered seven compounds that met the requirements, and tested those compounds in live cells to gauge their effects on catecholamines. Based on their findings, they tried one compound (TKO-10-18) on hypertensive mice, and showed that this compound produced the same anti-hypertensive effect as catestatin.

“Analysis of the catestatin molecule yielded a family of small organic compounds with preserved potency and pathway specificity,” said Valentina Kouznetsova, PhD, an associate project scientist at SDSC and the UC San Diego Moores Cancer Center. “Further refinement of our model should lead to the synthesis and development of a novel class of antihypertensive agents.”

Authors include SDSC’s Tsigelny, O’Connor, and Kouznetsova, as well as Nilima Biswas and Sushil K. Mahata, of UC San Diego’s Departments of Medicine and Pharmacology.

Media Contact

Cassie Ferguson, casferguson@gmail.com
Secondary media contact:
Jan Zverina, 858-534-5111, jzverina@sdsc.edu

Cassie Ferguson | EurekAlert!
Further information:
http://www.ucsd.edu/
http://ucsdnews.ucsd.edu/pressrelease/studies_suggest_new_key_to_switching_off_hypertension

Further reports about: Cancer blood pressure blood vessel hypertension risk factor

More articles from Life Sciences:

nachricht Scientists discover genetic switch that can prevent peripheral vascular disease in mice
29.07.2014 | University of Texas Health Science Center at Houston

nachricht Mineral magic? Common mineral capable of making and breaking bonds
29.07.2014 | Arizona State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Anzeige

Anzeige

Event News

Counting down to FEBS-EMBO 2014 in Paris, France

29.07.2014 | Event News

9th European Wood-Based Panel Symposium 2014 – meeting point for the wood-based material branch

24.07.2014 | Event News

“Lens on Life” - Artists and Scientists Explore Cell Divison

08.07.2014 | Event News

 
Latest News

Scientists discover genetic switch that can prevent peripheral vascular disease in mice

29.07.2014 | Life Sciences

From Finding Nemo to minerals – what riches lie in the deep sea?

29.07.2014 | Earth Sciences

Physicists unlock nature of high-temperature superconductivity

29.07.2014 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>