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TitleFunctionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 942, Year 2022
Publish dateFeb 17, 2022
AuthorsMargaret Wu / Ester Carballo-Jane / Haihong Zhou / Peter Zafian / Ge Dai / Mindy Liu / Julie Lao / Terri Kelly / Dan Shao / Judith Gorski / Dmitri Pissarnitski / Ahmet Kekec / Ying Chen / Stephen F Previs / Giovanna Scapin / Yacob Gomez-Llorente / Scott A Hollingsworth / Lin Yan / Danqing Feng / Pei Huo / Geoffrey Walford / Mark D Erion / David E Kelley / Songnian Lin / James Mu /
PubMed AbstractInsulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, ...Insulin analogs have been developed to treat diabetes with focus primarily on improving the time action profile without affecting ligand-receptor interaction or functional selectivity. As a result, inherent liabilities (e.g. hypoglycemia) of injectable insulin continue to limit the true therapeutic potential of related agents. Insulin dimers were synthesized to investigate whether partial agonism of the insulin receptor (IR) tyrosine kinase is achievable, and to explore the potential for tissue-selective systemic insulin pharmacology. The insulin dimers induced distinct IR conformational changes compared to native monomeric insulin and substrate phosphorylation assays demonstrated partial agonism. Structurally distinct dimers with differences in conjugation sites and linkers were prepared to deliver desirable IR partial agonist (IRPA). Systemic infusions of a B29-B29 dimer in vivo revealed sharp differences compared to native insulin. Suppression of hepatic glucose production and lipolysis were like that attained with regular insulin, albeit with a distinctly shallower dose-response. In contrast, there was highly attenuated stimulation of glucose uptake into muscle. Mechanistic studies indicated that IRPAs exploit tissue differences in receptor density and have additional distinctions pertaining to drug clearance and distribution. The hepato-adipose selective action of IRPAs is a potentially safer approach for treatment of diabetes.
External linksNat Commun / PubMed:35177603 / PubMed Central
MethodsEM (single particle)
Resolution4.5 - 5.2 Å
Structure data

23766

7md4

EMDB-23766, PDB-7md4:
Insulin receptor ectodomain dimer complexed with two IRPA-3 partial agonists
Method: EM (single particle) / Resolution: 4.5 Å

23767

7md5

EMDB-23767, PDB-7md5:
Insulin receptor ectodomain dimer complexed with two IRPA-9 partial agonists
Method: EM (single particle) / Resolution: 5.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
KeywordsPEPTIDE BINDING PROTEIN / Insulin receptor

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