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Insulin mimetic L-783,281

from Pseudomassaria sp.

Insulin, mature form with disulfide-bridge linked chains

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In other tissues the signal substance insulin is bound to insulin receptors. The insulin receptor is a tetramer (alpha2/beta2) with the alpha subunits being located at the cell surface. The beta subunits span the cytoplasmic membrane and contain a cytoplasmic domain with the function of a tyrosine protein kinase. Upon binding of insulin to the alpha subunits this domain is triggered to be autophosphorylated. The phosphorylation of three tyrosines in the activation loop enables the kinase to phosphorylate other proteins (a short peptide shown only) at the expense of ATP (replaced here by an uncleavable analog). Primary targets are the insulin receptor substrate proteins (IRS), the phosphorylation of which sets on the modification of a web of interacting proteins, which eventually regulate the energy metabolism.

A regulation scheme as complex as this is prone to failure. The disease associated with the lack of the signalling function of insulin is diabetes in various forms depending on the kind of failure. It affects ~5% of the population. Type 1 diabetes descibes a lack of insulin production due to autoimmune destruction of the producing cells. Insulin has to be supplied exogeneously by injection to keep the regulation of glucose metabolism balanced. In type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM) the receptors no longer respond properly to the presence of insulin.

In an effort to ease the treatment of diabetes, upon screening >50 000 mixtures of various origins a substance was found, which stimulated the kinase activity of the insulin receptor in the absence of insulin. This substance (L-738,281, shown here a simulated model) is a substituted quinone produced by a fungus (Pseudomassaria sp.) found on leaves of a plant near Kinshasa (Kongo). The stimulation was found in cell cultures (Chinese hamster ovary cells) expressing human insulin receptor, but not in those expressing related receptor tyrosine kinases. In vivo efficacy of L-783,281 could be demonstrated by feeding the substance to mutant mice serving as models for NIDDM.

Several experimental results indicate that L-738,281 circumvents the signalling mechanism within the insulin receptor by directly interacting with the kinase domain. It seems by binding to the protein to alter the conformation near Lys1030 which is part of the ATP binding site. This structural change triggers the autophosphorylation process like the binding of insulin on the opposite side of the membrane.

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insulin
insulin receptor tyrosine kinase domain
L-738,281
insulin receptor substrate-1

substrate fragment

Update

While L-783,281 (now termed asterriquinone) induced further search for orally usable insulin mimetics, this substance turned out to bind to other receptors as well resulting in unwanted side effects. Still useful for research on insulin action, it never made it to clinical trials for human therapy.