Naturally occurring molecule rivals Ozempic in weight loss, sidesteps side effects

Good news! Just amazing how many medications to reduce weight have become available so quickly in a short time.

"A naturally occurring molecule identified by Stanford Medicine researchers appears similar to semaglutide—also known as Ozempic—in suppressing appetite and reducing body weight. Notably, testing in animals also showed that it worked without some of the drug's side effects, such as nausea, constipation and significant loss of muscle mass. 

The newly discovered molecule, BRP, acts through a separate but similar metabolic pathway and activates different neurons in the brain — seemingly offering a more targeted approach to body weight reduction. ...

Instead of manually isolating proteins and peptides from tissues and using techniques like mass spectrometry to identify hundreds of thousands of peptides, the researchers designed a computer algorithm they named Peptide Predictor to identify typical prohormone convertase cleavage sites in all 20,000 human protein-coding genes. They then focused on genes that encode proteins that are secreted outside the cell — a key characteristic of hormones — and that have four or more possible cleavage sites. Doing so narrowed down the search to 373 prohormones, a manageable number to screen for their biological effects. ...

Peptide Predictor predicted that prohormone convertase 1/3 would generate 2,683 unique peptides from the 373 proteins. ... focused on sequences likely to be biologically active in the brain. They screened 100 peptides, including GLP-1, for their ability to activate lab-grown neuronal cells.

As expected, the GLP-1 peptide had a robust effect on the neuronal cells, increasing their activity threefold over control cells. But a small peptide made up of just 12 amino acids bumped up the cells’ activity tenfold over controls. The researchers named this peptide BRP based on its parent prohormone, BPM/retinoic acid inducible neural specific 2, or BRINP2 (BRINP2-related-peptide).

When the researchers tested the effect of BRP on lean mice and minipigs ... they found that an intramuscular injection of BRP prior to feeding reduced food intake over the next hour by up to 50% in both animal models. Obese mice treated with daily injections of BRP for 14 days lost an average of 3 grams — due almost entirely to fat loss — while control animals gained about 3 grams over the same period. The mice also demonstrated improved glucose and insulin tolerance. ..."

From the abstract:

"Peptide hormones, a class of pharmacologically active molecules, have a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (also known as PCSK1/3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide 1 (GLP-1). However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown.

Here we use computational drug discovery to systematically map more than 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified a 12-mer peptide, BRINP2-related peptide (BRP). When administered pharmacologically, BRP reduces food intake and exhibits anti-obesity effects in mice and pigs without inducing nausea or aversion. Mechanistically, BRP administration triggers central FOS activation and acts independently of leptin, GLP-1 receptor and melanocortin 4 receptor. Together, these data introduce a method to identify new bioactive peptides and establish pharmacologically that BRP may be useful for therapeutic modulation of body weight."

Naturally occurring molecule rivals Ozempic in weight loss, sidesteps side effects

Naturally occurring molecule rivals Ozempic in weight loss, sidesteps side effects (original news release)

Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide (no public access)

Katrin Svensson, senior author. "Svensson has co-founded a company to launch clinical trials of the molecule in humans in the near future."

The 12-amino-acid BRP peptide (spheres are atoms and sticks are bonds) suppresses appetite and reduces weight gain in mice and pigs without causing nausea or food aversion.