Treatment of diabetes, toll-like receptor 4 modulators and methods for using the same
Inventors
Siu, Leung-Kei • Chong, Pele Choi-Sing • Chang, Feng-Yee • Leng, Chih-Hsiang
Assignees
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Publication Number
US-10287328-B2
Publication Date
2019-05-14
Expiration Date
Abstract
The present invention relates to treatment of diabetes, toll-like receptor 4 (TLR-4) modulators and methods for using the same. Particularly, the present invention provides an isolated peptide from pneumolysin (PLY peptide) which is effective in treatment of diabetes. In addition, the PLY peptide of the present invention is a TLR-4 antagonist and thus can be used in the treatment of a disease or condition associated with TLR-4 activation. The present invention also provides treatment of diabetes with a TLR-4 antagonist.
Core Innovation
The invention relates to pneumolysin (PLY) peptide fragments that function as TLR-4 antagonists when administered to a subject in need thereof. The disclosed PLY peptides comprise a first segment containing the amino acid sequence QDLTA (SEQ ID NO: 9) and a second segment containing an amino acid sequence at least 90% identical to SEQ ID NO: 10, with the C-terminus of the first segment linked to the N-terminus of the second segment. The total length of the PLY peptide is up to 150 amino acids.
The invention addresses the problem of inhibiting toll-like receptor 4 (TLR-4) activity in a subject to treat TLR-4-associated inflammatory diseases. In particular, the disclosed truncated PLY peptides are described as agents for diabetes (notably type II) and TLR-4-associated inflammatory diseases including atherosclerosis. The document further ties the peptide structure to functional outcomes associated with TLR-4 activity and TLR-4-mediated inflammation.
Mechanistically, the invention is described as blocking TLR-4 activation by inhibiting the interaction of MD2 protein with TLR-4, including through binding/competition with LPS-associated signaling. The truncated PLY peptides are described to reduce downstream signaling associated with ERK1/2 and NF-κB-p65, and to attenuate inflammatory cell behavior, including inhibition of LPS-induced neutrophil transmigration. The document also describes reduced cytotoxicity/apoptosis relative to full-length PLY.
Claims Coverage
The independent claim defines a method of inhibiting TLR-4 activity in a subject using a specific two-segment truncated pneumolysin (PLY) peptide structure. The scope is anchored by the QDLTA (SEQ ID NO: 9) first segment linked to a second segment at least 90% identical to SEQ ID NO: 10, with the total peptide length up to 150 amino acids. Dependent claims further refine sequence identity, mutation limits, and disease/mechanistic context.
Two-segment linked truncated PLY peptide for TLR-4 inhibition
A method for inhibiting the activity of toll-like receptor 4 (TLR-4) in a subject by administering an effective amount of a pneumolysin (PLY) peptide comprising (i) a first segment comprising QDLTA (SEQ ID NO: 9) and (ii) a second segment comprising an amino acid sequence at least 90% identical to SEQ ID NO: 10, with the C-terminus of the first segment linked to the N-terminus of the second segment, wherein the PLY peptide is up to 150 amino acids in length.
Higher sequence identity for the second segment
The method where the second segment of the PLY peptide contains an amino acid sequence at least 97% identical to SEQ ID NO: 10.
Limited mutations in the second segment
The method where the second segment of the PLY peptide contains mutations at up to 2 amino acid residues as given in SEQ ID NO: 10.
Specific residue substitutions at positions 19 and/or 20
The method where the amino acid residue substitution includes I19L, R20K, or a combination of these.
Blocking MD2 binding to TLR-4
The method that includes using a PLY peptide to block binding of an MD2 protein to TLR-4.
Atherosclerosis as the TLR-4 activation–associated inflammatory disorder
The method where the inflammatory disorder caused by TLR4 activation is atherosclerosis.
Overall, the claim set is directed to TLR-4 inhibition via administration of a truncated, two-segment linked PLY peptide defined by QDLTA (SEQ ID NO: 9) and a second segment at least 90% identical to SEQ ID NO: 10, with additional claim refinements specifying higher identity, limited and specified mutations, and mechanistic and disease embodiment elements including blockade of MD2 binding to TLR-4 and the inflammatory disorder being atherosclerosis.
Stated Advantages
Inhibits TLR-4 activity in a subject.
Blocks TLR-4 activation associated with downstream signaling, including reduced ERK1/2 and NF-κB-p65 signaling.
Attenuates inflammatory responses associated with TLR-4 activity, including reduced LPS-induced neutrophil transmigration.
Reduces blood glucose and increases insulin in the described diabetes contexts.
Decreases serum ICAM-1/VCAM-1/E-selectin and attenuates neointima/atherosclerotic status.
Exhibits reduced cytotoxicity/apoptosis compared to full-length PLY.
Documented Applications
Treatment or inhibition of TLR-4-associated inflammatory diseases, including diabetes (type II) and atherosclerosis.
Inhibition of LPS-induced neutrophil transmigration via TLR-4 antagonism.
Use of the truncated PLY peptides in biological contexts described for TLR-4 activation–associated inflammatory disorders including effects on ICAM-1, VCAM-1, E-selectin, and atherosclerotic status.
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