Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics
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Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics. / Paternoster, Silvano; Simpson, Peter V.; Kokh, Elena; Kizilkaya, Hüsün Sheyma; Rosenkilde, Mette Marie; Mancera, Ricardo L.; Keating, Damien J.; Massi, Massimiliano; Falasca, Marco.
In: Pharmacological Research, Vol. 172, 105822, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics
AU - Paternoster, Silvano
AU - Simpson, Peter V.
AU - Kokh, Elena
AU - Kizilkaya, Hüsün Sheyma
AU - Rosenkilde, Mette Marie
AU - Mancera, Ricardo L.
AU - Keating, Damien J.
AU - Massi, Massimiliano
AU - Falasca, Marco
N1 - Publisher Copyright: © 2021 Elsevier Ltd
PY - 2021
Y1 - 2021
N2 - Metabolic diseases, such as obesity and type 2 diabetes, are relentlessly spreading worldwide. The beginning of the 21st century has seen the introduction of mechanistically novel types of drugs, aimed primarily at keeping these pathologies under control. In particular, an important family of therapeutics exploits the beneficial physiology of the gut-derived glucagon-like peptide-1 (GLP-1), with important clinical benefits, from glycaemic control to cardioprotection. Nonetheless, these protein-based drugs act systemically as exogenous GLP-1 mimetics and are not exempt from side effects. The food-derived lipid oleoyl-lysophosphatidylinositol (LPI) is a potent GPR119-dependent GLP-1 secreting agent. Here we present a structure-activity relationship (SAR) study of a synthetic library of oleoyl-LPI mimetics capable to induce the physiological release of GLP-1 from gastrointestinal enteroendocrine cells (EECs). The best lead compounds have shown potent and efficient release of GLP-1 in vitro from human and murine cells, and in vivo in diabetic db/db mice. We have also generated a molecular model of oleoyl-LPI, as well as its best performing analogues, interacting with the orthosteric site of GPR119, laying foundational evidence for their pharmacological activity.
AB - Metabolic diseases, such as obesity and type 2 diabetes, are relentlessly spreading worldwide. The beginning of the 21st century has seen the introduction of mechanistically novel types of drugs, aimed primarily at keeping these pathologies under control. In particular, an important family of therapeutics exploits the beneficial physiology of the gut-derived glucagon-like peptide-1 (GLP-1), with important clinical benefits, from glycaemic control to cardioprotection. Nonetheless, these protein-based drugs act systemically as exogenous GLP-1 mimetics and are not exempt from side effects. The food-derived lipid oleoyl-lysophosphatidylinositol (LPI) is a potent GPR119-dependent GLP-1 secreting agent. Here we present a structure-activity relationship (SAR) study of a synthetic library of oleoyl-LPI mimetics capable to induce the physiological release of GLP-1 from gastrointestinal enteroendocrine cells (EECs). The best lead compounds have shown potent and efficient release of GLP-1 in vitro from human and murine cells, and in vivo in diabetic db/db mice. We have also generated a molecular model of oleoyl-LPI, as well as its best performing analogues, interacting with the orthosteric site of GPR119, laying foundational evidence for their pharmacological activity.
KW - Enteroendocrine cells
KW - Glucagon-like peptide-1
KW - GPR119
KW - Oleoyl-lysophosphatidylinositol
KW - Tetrazoles
KW - Type 2 diabetes
U2 - 10.1016/j.phrs.2021.105822
DO - 10.1016/j.phrs.2021.105822
M3 - Journal article
C2 - 34411732
AN - SCOPUS:85113420838
VL - 172
JO - Pharmacological Research
JF - Pharmacological Research
SN - 1043-6618
M1 - 105822
ER -
ID: 281604312