# A Robust Platform for Design and Development of Therapeutic Peptides for Metabolic Syndrome

> **NIH NIH R42** · VELUM, INC. · 2024 · $1,135,509

## Abstract

Project Summary
There is a world-wide “twin epidemic” of obesity and Type 2 Diabetes (T2D), with an urgent need to find new
drug treatments that induce weight loss and correct the concurrent metabolic dysfunction, including
hyperglycemia. Stable derivatives of the endogenous enteroendocrine hormone, glucagon-like peptide-1
(GLP1), are in clinical use for the treatment of T2D and have more recently also been approved for the treatment
of obesity.
However, efficacy of even the most advanced GLP1-based drugs remains modest compared to what can be
achieved by bariatric surgery, an invasive procedure that carries considerable risks but results in rapid and
sustained normalization of blood glucose and then body weight. The therapeutic effects of bariatric surgery
appear to rely on the simultaneous, synergistic modulation of many different endogenous glucoregulatory
hormones. Inspired by this observation, there are now ongoing efforts to combine GLP1 treatment with
stimulation of other hormonal regulatory pathways of metabolism, which has been shown to further increase
treatment efficacy.
One promising pathway that could be co-targeted relies on the hormone peptide tyrosine tyrosine (PYY), which
is physiologically co-secreted from intestinal endocrine cells together with GLP1. However, PYY is rapidly N-
terminally cleaved in the blood stream by the ubiquitous enzyme dipeptidyl-peptidase-4 (DPP4). As a result of
this truncation, PYY loses its ability to stimulate one of its targets, the neuropeptide Y1 receptor (NPY1R) which
mediates the hormone’s beneficial effects on islet integrity, insulin production, and maintenance of glucose
homeostasis. While truncated PYY maintains its ability to stimulate a complementary target, the anorexic
NPY2R in the brain, its therapeutic promise is diminished given the loss of concomitant NPY1R agonism.
In phase 1 studies leading to the current proposal, we have been able, for the first time, to N-terminally modify
PYY in a way that eliminates susceptibility to DPP4 and fully preserves this peptide’s ability to stimulate both
NPY1Rs and NPY2Rs. The main goal of the current phase 2 proposal is to take the next steps to transform this
stabilized NPY1R/NPY2R dual agonist into a drug, which requires further optimization to enable once-daily
dosing (Aim 1) and demonstrating efficacy in protecting islet function and in reducing obesity in mouse models
(Aim 2). These studies will set the stage for us to subsequently apply for IND-enabling studies. Such studies
would be to pursue further development into a dual NPY1R/NPY2R companion drug, one that can be applied
together with GLP1-based as well as related treatments for enhancing the treatment of diabesity. In
complementary experiments, we will also explore integrating PYY functionality into recently reported
monomolecular multi-agonists that are designed to, in addition to the GLP1R, simultaneously activate distinct
receptors for one or two other, synergistic hormones (Aim 3). T...

## Key facts

- **NIH application ID:** 10922108
- **Project number:** 2R42DK131842-02
- **Recipient organization:** VELUM, INC.
- **Principal Investigator:** Martin Beinborn
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,135,509
- **Award type:** 2
- **Project period:** 2022-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922108

## Citation

> US National Institutes of Health, RePORTER application 10922108, A Robust Platform for Design and Development of Therapeutic Peptides for Metabolic Syndrome (2R42DK131842-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10922108. Licensed CC0.

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