Synthetic peptide may offer better treatment option for high blood pressure

Researchers from the University of Vermont have developed synthetic peptides that offer a potential new therapeutic target for the treatment of hypertension, due to their ability to prevent the blood vessel constriction that results in high blood pressure. Because the peptides only seem to affect damaged arterial vessels, with no effect on healthy vessels, a resulting treatment could have fewer side effects than current drug options.

These findings were recently published in the journal Chemistry & Biology, and the researchers also received a United States patent for the new synthetic peptides.

The costs of hypertension

Hypertension, also known as high blood pressure, occurs when blood flows through the body’s arteries with a greater force than normal.  The condition affects about 70 million Americans, or roughly one in three adults in the United States, and is a significant risk factor for cardiovascular and kidney disease.

According to a Centers for Disease Control infographic, someone with high blood pressure is four times more likely to die from a stroke and three times more likely to die from heart disease. Hypertension contributes to around 1,000 deaths per day in the United States and costs the nation an estimated $51 billion each year.

There are currently many available treatment options for hypertension, ranging from beta blockers to angiotensin-converting enzyme (ACE) inhibitors to thiazide diuretics, yet only about half the people with high blood pressure have their condition under control. As a result, researchers continue to seek new approaches to treating high blood pressure.

A serendipitous discovery

The University of Vermont researchers, led by Dr. Wolfgang Dostmann, did not set out to develop the new peptides. The team studies how muscle cells in blood vessels constrict and dilate. As part of this work, they solved the structure of protein kinase 1alpha (PKG 1α), a cGMP-dependent protein kinase that phosphorylates various biologically important targets. The kinase has been implicated in regulating smooth muscle relaxation, as well as cell division, nucleic acid synthesis and more.

“This therapeutic pathway has huge potential for the average person.”

“Solving this structure improved our understanding of how this enzyme is turned on and off,” said Dr. Dostmann in a press release. They theorized that the kinase could be regulated not only by its natural activator – the second messenger cGMP – but also by specifically designed synthetic peptides. The team then created short synthetic peptides, termed “S-tides”, with the ability to modulate PKG 1α activity.

 The researchers applied the S-tides directly to animal model arteries and found they activated PKG 1α, as well as signaling molecules related to the kinase’s activation. As a result, the pressure-induced constriction of the vessels that causes hypertension was prevented. Of particular interest was that the S-tides only affected the vessels if the tissue lining the blood side was damaged (as it is in atherosclerosis, a common condition in which plaque builds up in the arteries). There was no effect on the healthy vessels.

The therapeutic potential

“This therapeutic pathway has huge potential for the average person,” Dr. Dostmann said. He added that other drugs also work on the PKG 1α signaling pathway, such as nitroglycerine and Viagra, which was initially used to treat blood pressure. However, these existing drugs are all designed to activate PKG by keeping intracellular cGMP at a higher level. S-tides, in contrast, don’t change the levels of cGMP.

PKG-targeted therapies could also help treat conditions beyond high blood pressure, as the kinase has been shown to be relevant in cancer, obesity and all forms of cardiovascular disease. The researchers’ discovery offers “a first step for creating a platform from which pharmaceutical therapies can be designed,” Dr. Dostmann said. 

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