The Story of SNAP

HIMERIA is a biotechnology company focusing on the development of SNAP, a “first-in-class” activator of PHLPP1, a critical phosphatase at the crossroads of some of biology’s most important networks, including those of AKT, mTOR-S6K and ERK1/2.

PHLPP1 directly dephosphorylates and inhibits p-AKT, p-S6K1, p-ERK1/2, p-STAT-1 and p-histone 3. These networks determine critical cellular functions based on the availability of fuel (like oxygen, glucose, lipids, amino acids), including proliferation (growth), apoptosis (death), altered metabolism (oxidative phosphorylation versus glycolysis versus the “pentose phosphate pathway”), inflammation, or Epithelial-to-Mesenchymal Transition (EMT). These functions regulate many cellular responses to environmental or genetic stresses and determine survival of normal tissues to ischemia or ischemia-reperfusion (IR) or the ability of cancer cells to survive chemotherapy or radiation therapy or undergo EMT and metastasize.

Discovery of SNAP: Using an animal model of hibernation in snails, we discovered, for the first time, a Hibernation-Inducing Factor (HnIF). This small molecule was present in the metabolome of hibernating (but not non-hibernating) snails and not in the metabolome of species that cannot hibernate (like mice or humans). Computer modeling showed that this HnIF binds to an allosteric pocket of PHLPP1, a conserved phosphatase that is present in all cellular compartments of all known species, including snails, yeast, mice and humans. This binding was predicted to increase PHLPP1 activity. We synthesized this HnIF chemically and we named it SNAP (Snail Activator of PHLPP1). In mice/human cell lysates, SNAP activated PHLPP1 without activating other cellular phosphatases. Ex cellulo, SNAP activated human recombinant PHLPP1. SNAP did not increase phosphate release when PHLPP1 was knocked out, or when its PHLPP1 binding site was mutated, proving that SNAP is a “first-in-class” PHLPP1 activator.

SNAP applications

1) Resistance of normal cells to ischemia or IR, major causes of death in humans or damage to organs offered for transplantation (IR damage of a donated organ during the transfer and placement to a recipient is a major challenge in transplant medicine). SNAP increases survival and limits damage in fibroblasts and cardiomyocytes exposed to ischemia and IR. In a model of mouse hearts mimicking the ischemic and IR damage to donated organs transferred and placed in a recipient, SNAP preserved heart function.

First, SNAP can be immediately perfused to donated organs to increase their “shelf-life” by inducing a state of hibernation as it does in snails. During hibernation, animals tolerate the ischemia from the very low heart and respiratory rates during hibernation or the IR upon exiting hibernation, without any organ damage. Thus, SNAP represents the first direct application of hibernation biology to non-hibernating species.

Second, SNAP can limit the IR damage in patients with coronary artery disease and heart attacks undergoing coronary interventions or bypass surgery.

2) Human hibernation in ultra-long space travel. SNAP injections induced reversible hibernation in snails that was indistinguishable from naturally induced hibernation. As PHLPP1 is present in all human organs and tissues, it may be able to induce a hibernation state in astronauts as well. Similarly, it may be able to induce hibernation and protect from stress-induced injury in patients suffering from serious conditions like septic or hemorrhagic shock, preventing ongoing damage from ischemia or inflammation.

3) Longevity: During hibernation, animals exhibit decreased ageing rates, in keeping with PHLPP1’s ability to inhibit mTOR-S6K (like rapamycin). SNAP’s chronic effects may include slowing the ageing process and thus delaying the appearance of several age-related chronic diseases. SNAP decreases chronological age in yeast and inhibits senescence in mammalian cells exposed to stress. SNAP may be similar to other drugs that appear to improve longevity and decrease both ischemia and IR damage in the heart while they inhibit cancer as well, like metformin, SGLT2 inhibitors or Ozempic. Intriguingly, by inhibiting p-AKT, SNAP has glucose-decreasing properties as well, similarly to all above classes of drugs that were first known as anti-diabetic, before all their other effects on the heart, cancer and longevity were realized.

4) Other Future Applications Include:

a) Pulmonary Arterial Hypertension: a deadly vascular disease where SNAP shows promise in reversing it in animal models.

b) Cancer: PHLPP1 is a recognized anti-oncoprotein in prostate and other cancers and SNAP shows promise in animal and human tissues (cancer organoids).