Target for diabetes treatment and prevention
Inventors
Marion, Vincent • Petrovsky, Nikolai
Assignees
VAXINE Pty Ltd • Institut National de la Sante et de la Recherche Medicale INSERM • Universite de Strasbourg
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Publication Number
US-10821159-B2
Publication Date
2020-11-03
Expiration Date
Abstract
The present invention relates to the identification of ALMS1 as the missing player involved in the regulation of the insulin-mediated glucose uptake through GLUT4 sorting vesicles, and to the down-regulation of ALMS1 by αPKC. Accordingly, the present invention relates to a molecule capable of preventing the binding of αPKC on ALMS1 for use for treating or preventing diabetes, in particular type 2 diabetes. In addition, the present invention relates to a method for identifying molecule capable of preventing the binding of αPKC on ALMS1.
Core Innovation
The invention centers on ALMS1 (Alstrom syndrome protein 1) regulation of insulin-mediated GLUT4 glucose uptake in adipocytes through ALMSome function. It identifies that binding of αPKC (Protein Kinase C alpha type) to ALMS1 downregulates ALMSome function, including acidification/proton pump-dependent GLUT4 vesicle fusion, whereas TBC1D4 binding to ALMS1 activates or allows GLUT4 trafficking.
To address insulin signaling and glucose uptake defects, the invention proposes administering molecules that prevent αPKC–ALMS1 binding, thereby counteracting the downregulation of ALMSome function. The molecules are described as peptides and mimetics, including ALMS1-derived and αPKC-derived sequences, and stapled peptides designed to inhibit the binding interface, with the stated aim to treat or delay diabetes and related complications.
The document further describes screening and identification approaches for such binding-inhibitory molecules using binding assays for αPKC–ALMS1 and TBC1D4–ALMS1, as well as cellular insulin-responsive systems. It also describes in silico structural homology modeling and docking to support rational peptide design, and modulation of ALMS1 expression or TBC1D4 binding.
Claims Coverage
The independent claims cover three core inventive features. They share a common inventive feature set centered on administering a peptide that inhibits αPKC binding to ALMS1, specifying the peptide as SEQ ID NO: 14, optionally stapled.
Peptide inhibiting αPKC binding to ALMS1
Administering a peptide that inhibits the binding of αPKC (Protein Kinase C alpha type) to ALMS1 (Alstrom syndrome protein 1), wherein the peptide consists of SEQ ID NO: 14 or is a stapled peptide consisting of SEQ ID NO: 14.
Treating or delaying diabetes-related conditions by αPKC–ALMS1 binding inhibition
Treating or delaying the progression or onset of diabetes mellitus, insulin resistance, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, obesity, or hyperinsulinaemia in a subject in need thereof by administering a peptide that inhibits αPKC binding to ALMS1 as defined by SEQ ID NO: 14 or a stapled peptide consisting of SEQ ID NO: 14.
Stimulating glucose uptake by adipocytes by αPKC–ALMS1 binding inhibition
Stimulating glucose uptake by adipocytes in a subject in need thereof by administering a peptide that inhibits αPKC binding to ALMS1 as defined by SEQ ID NO: 14 or a stapled peptide consisting of SEQ ID NO: 14.
Overall, the claims are directed to therapeutic and glucose-uptake functional effects achieved by administering an αPKC–ALMS1 binding-inhibitory peptide based on SEQ ID NO: 14, with dependent claim refinements specifying type 2 diabetes mellitus and whether the SEQ ID NO: 14 peptide is stapled.
Stated Advantages
Treating or delaying the progression or onset of diabetes mellitus and related conditions including insulin resistance, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, obesity, and hyperinsulinaemia.
Stimulating glucose uptake by adipocytes.
Documented Applications
Treating or delaying progression or onset of diabetes mellitus, insulin resistance, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, hyperglycemia, obesity, or hyperinsulinaemia in a subject.
Stimulating glucose uptake by adipocytes in a subject.
Rational peptide design and identification/screening of molecules that inhibit αPKC–ALMS1 binding, using αPKC–ALMS1 and TBC1D4–ALMS1 binding assays, cellular insulin-responsive systems, and in silico structural homology modeling/docking.
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