Studies suggest new key to 'switching off' hypertension

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.

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.

Most Popular Now

AstraZeneca divests rights for Losec to Cheplaphar…

AstraZeneca has agreed to sell the global commercial rights, excluding China, Japan, the US and Mexico, for Losec (omeprazole) and associated brands to Cheplapharm Arznei...

Bayer, Brigham and Women’s Hospital, and Massachus…

Bayer and Partners HealthCare's founding members Brigham and Women's Hospital (BWH) and Massachusetts General Hospital (MGH) today announced the launch of a joint lab to ...

Amgen announces positive results from two Phase 3 …

Amgen (NASDAQ:AMGN) today announced that the results of a prespecified interim analysis of an open-label, randomized, controlled global multicenter Phase 3 trial (2012021...

Cause of antibiotic resistance identified

Scientists have confirmed for the first time that bacteria can change form to avoid being detected by antibiotics in the human body. Studying samples from elderly patient...

Brilinta monotherapy in high-bleeding risk patient…

New data from TWILIGHT, a Phase IV independent trial (funded by AstraZeneca), showed that in patients at high-bleeding risk who underwent PCI and completed 3 months of du...

Novartis and Microsoft announce collaboration to t…

Novartis announced an important step in reimagining medicine by founding the Novartis AI innovation lab and by selecting Microsoft as its strategic AI and data-science pa...

Bayer inks deals with eleven startups under G4A Di…

Bayer announced today that the company has signed collaboration agreements with eleven digital health startups. As part of the program, Bayer will support these startup c...

Ian Read to retire as Executive Chairman of Pfizer…

Following its regularly scheduled meeting, the Board of Directors of Pfizer Inc. (NYSE:PFE) today announced that Executive Chairman of the Board Ian C. Read has chosen to...

Discovery of new source of cancer antigens may exp…

For more than a decade, scientist Stephen Albert Johnston and his team at Arizona State University's Biodesign Institute have pooled their energies into an often scoffed-...

Pharmacists provide patient value in team-based ca…

With inhaler in hand, Dr. Cheng Yuet went over every detail to make sure the patient understood how the drug would control their COPD symptoms. Dr. Yuet is proving what a...

Chinese activists protest the use of traditional t…

In the West, the number of people challenging scientific authority has been growing in past decades. This has, among other things, led to a decline in the support for mas...

AI and big data predict which research will influe…

An artificial intelligence/machine learning model to predict which scientific advances are likely to eventually translate to the clinic has been developed by Ian Hutchins...