# Discovery and design of novel insulin evologs from venomous marine cone snails

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $352,640

## Abstract

SUMMARY
Insulin is a pancreatic peptide hormone that is of critical importance for glucose homeostasis. Disruption
of insulin production or function can result in diabetes mellitus. Insulin therapy is the only effective treatment
for type 1 diabetes (T1D) and is used by many people with type 2 diabetes (T2D) and some individuals
with gestational diabetes (GDM). Despite major advances in insulin therapy, achieving efficient glycemic
control to prevent short- and long-term complications remains a major challenge in diabetes management.
This is in part due to the fact that insulin and its current therapeutic analogs self-associate into dimers and
hexamers that form subcutaneous depots, which delays their onset of action and leads to prolonged
duration of action. Our recent discovery of specialized monomeric insulins from the venom of fish-hunting
cone snails that rapidly lower blood glucose in animal models of diabetes provides the unique opportunity
to address these persistent limitations of current diabetes therapeutics. Furthermore, shaped by millions
of years of predator-prey evolution, venom insulins have evolved unique ways of engaging with the
vertebrate insulin receptor (hIR), thus providing a unique toolset to study diverse molecular modes of hIR
activation. Proof of concept for the high translational impact of this proposal is provided by Con-Insulin
G1, our first discovered venom insulins that revealed the existence of a minimized insulin binding motif at
the hIR and has already led to the design of a new therapeutic prandial insulin candidate. Our recent
preliminary data demonstrates that Con-Ins G1 is only one of > 20 diverse insulins evolved by fish-hunting
cone snails. We hypothesize that each one of these insulins represents a novel scaffold for the rational
design of improved insulin therapeutics. The aim of this proposal is to survey the entire chemical diversity
of naturally evolved insulin analogs (so-called evologs) for the discovery and development of new insulin
drug candidates with advantageous properties over existing analogs (i.e., improved stability profiles, faster
onset of action, reduced rates of post-injection hypoglycemia, and potentially improved metabolic
signaling). We anticipate that these candidates have the potential to significantly improve diabetes therapy
and enhance the performance of closed-loop systems in the future.

## Key facts

- **NIH application ID:** 10859370
- **Project number:** 1R01DK139317-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Helena Safavi-Hemami
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $352,640
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859370

## Citation

> US National Institutes of Health, RePORTER application 10859370, Discovery and design of novel insulin evologs from venomous marine cone snails (1R01DK139317-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10859370. Licensed CC0.

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