KR-20260068089-A - Detoxification peptides

Abstract

The present invention relates to a detoxification peptide for use in the treatment and/or prevention of disorders associated with glycosylation and/or glycooxidation of proteins and/or lipids, characterized in that the sequence comprises the following general amino acids: N-(Val-Gly-X1-X2-Pro-Gly)n-OH, wherein: N and OH correspond to the N-terminus and C-terminus of the peptide, respectively; X1 and X2 are selected from valine (Val), glycine (Gly), threonine (Thr), asparagine (Asn), glutamine (Gln), alanine (Ala), leucine (Leu), and isoleucine (Ile); and n is an integer from 1 to 3.

Inventors

• 쁘띠 알랭
• 리터 디디에
• 아브라함 장-다니엘

Assignees

• 리젠티스 파마

Dates

Publication Date

20260513

Application Date

20240902

Priority Date

20230905

Claims (14)

1. A detoxification peptide for use in the treatment and/or prevention of pathologies related to the glycosylation and/or glycooxidation of proteins and/or lipids associated with the accumulation of advanced glycosylation products (AGEs) in organ tissues, characterized in that the sequence comprises the following general amino acid sequence, wherein the detoxification peptide is capable of reducing AGEs in said tissues and/or promoting AGE degradation by activating a specific nuclear transcription factor pathway representing NRF2 factor or "nuclear factor erythrocyte 2-related factor 2": N-(Val-Gly-X1-X2-Pro-Gly)n-OH(where, - N and OH correspond to the N-terminus and C-terminus of the peptide, respectively; - X1 and X2 are selected from valine (Val), glycine (Gly), threonine (Thr), asparagine (Asn), glutamine (Gln), alanine (Ala), leucine (Leu) and isoleucine (Ile); - n is an integer from 1 to 3).
2. A detoxification peptide according to claim 1, wherein the activation of the NRF2 transcription factor induces the activation of genes involved in autophagy and/or lysosome and/or ubiquitin/proteasome and/or nedylation pathways.
3. A detoxification peptide for use in the treatment and/or prevention of pathology associated with glycosylation and/or glycosylation oxidation of proteins associated with the accumulation of glycosylated vimentin and/or carboxymethyllysine (CML) type AGEs in organ tissues, wherein the detoxification peptide is capable of reducing glycosylated vimentin and/or carboxymethyllysine (CML) by activation of the NRF2 factor pathway.
4. A detoxification peptide characterized by having the following general amino acid sequence in any one of claims 1 to 3: N-(Val-Gly-X1-X2-Pro-Gly)n-Arg-X3-Arg-X4-X5-X6-X7-OH (Here, - N and OH correspond to the N-terminus and C-terminus of the peptide, respectively; - X1 and X2 are selected from valine (Val), glycine (Gly), threonine (Thr), asparagine (Asn), glutamine (Gln), alanine (Ala), leucine (Leu) and isoleucine (Ile); - X3 and X4 are selected from valine (Val), serine (Ser), tyrosine (Tyr), alanine (Ala), glycine (Gly), arginine (Arg) and leucine (Leu); - X5, X6, and X7 are selected from isoleucine (Ile), leucine (Leu), valine (Val), alanine (Ala), glycine (Gly), and phenylalanine (Phe); - n is an integer from 1 to 3).
5. A detoxification peptide according to any one of claims 1 to 4, characterized by having SEQ ID NO: 12, i.e., N-(Val-Gly-Val-Ala-Pro-Gly)n-Arg-Val-Arg-Leu-Gly-Ile-Leu-OH, wherein N and OH correspond to the N-terminus and C-terminus of the peptide, respectively, and n is 3.
6. A detoxification peptide characterized by having a sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 13 to SEQ ID NO: 37, in any one of claims 1 to 4.
7. A detoxification peptide for use in the treatment and/or prevention of side effects of radiation therapy and/or chemotherapy in a patient with cancer, in any one of claims 1 to 6.
8. A detoxification peptide for use in the treatment and/or prevention of cutaneous fibrosis and/or liver fibrosis and/or non-alcoholic fatty liver disease (NASH) and/or liver carcinoma, in any one of claims 1 to 6.
9. A detoxification peptide for use in the treatment and/or prevention of skin pathologies such as psoriasis and/or dermatitis and/or eczema, in any one of claims 1 to 6.
10. A detoxification peptide for use in the treatment and/or prevention of diabetes and its complications, e.g., diabetic neuropathy, diabetic nephropathy, glaucoma, cataract, and diabetic retinopathy, in any one of claims 1 to 6.
11. A detoxification peptide for use in the treatment and/or prevention of cardiovascular pathology in any one of claims 1 to 6.
12. A detoxification peptide for use in the treatment and/or prevention of neurodegenerative pathologies, such as Alzheimer's disease and/or Parkinson's disease and/or multiple sclerosis (MS) and/or amyotrophic lateral sclerosis (ALS), in any one of claims 1 to 6.
13. A detoxification peptide characterized by being obtained by chemical synthesis in any one of claims 1 to 12.
14. A pharmaceutical composition for use in the treatment and/or prevention of pathologies associated with glycosylation and/or glycolytic oxidation of proteins and/or lipids, comprising at least one peptide defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Description

Detoxification peptides The present invention relates to a peptide that can be applied particularly in the field of pharmaceuticals. The peptide according to the present invention is composed of a peptide capable of performing a "detoxification" function more specifically, and can be primarily applied in the field of prevention and/or treatment of specific pathologies related to transcription factor NRF2 ("nuclear factor erythrocyte 2-related factor 2"), and the peptide of the present invention acts on the expression and/or translocation of NRF2, particularly leading to an increase in autophagy and, consequently, a reduction in toxic molecular compounds, particularly advanced glycation end products (AGEs) or ROS (reactive oxygen species). The process of glycooxidation occurs due to the combined effects of oxidation and saccharification. Glycation is a complex process involving spontaneous and slow non-enzymatic reactions that occur between the free amino group of a protein and a reducing sugar, such as glucose or ribose, to form an unstable Schiff base. These reversible reaction products subsequently undergo irreversible oxidation, polymerization, dehydration, and crosslinking reactions to produce advanced glycation products (AGEs). These products include carboxyethyllysine (CEL), carboxymethyllysine (CML), glyoxal-lysine dimer (GOLD), 3-deoxyglucosone lysine dimer (DOLD), pyrroline, fructolysine, glucosepan, pentosidine, argpyrimidine, pyrroline, hydroxymethylfurfural (HMF), Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)ornithine (MG-H1), and fructolysine (FL). Antiglycation research is a rapidly expanding area of interest in the field of health and medicine as it is increasingly recognized that AGEs can play an important role in the development of various chronic diseases such as diabetes, cardiovascular disease (ischemia, cardiac fibrosis, arteriopathy, etc.), cancer, organ fibrosis (liver, kidney, heart, etc.), Alzheimer's disease, and other neurodegenerative diseases (e.g., Parkinson's disease, amyotrophic lateral sclerosis, or multiple sclerosis). In addition, many studies have shown that AGEs are involved in certain skin-related pathologies, such as psoriasis or dermatitis. Therefore, it would be very beneficial to be able to identify active ingredients and propose compositions that can offset the long-term effects of AGE formation and prevent or treat AGE-related pathologies. Current therapeutic approaches to inhibit glycosylation, AGEs, and their effects are numerous and diverse. Some strategies involve the use of antiglycation agents, such as glycosylation inhibitors, metal chelators, and AGE-degrading enzymes. Nevertheless, research in this field is still in its early stages, and researchers are still struggling to understand the fundamental mechanisms of glycosylation and the roles specific molecules may play in inhibiting or reversing this process. Therefore, there remains a need for antiglycation compounds that are specific, effective, safe, and possess excellent bioavailability. For example, some fibrosis treatments have limitations and focus primarily on symptom control, reduction of complications, and slowing disease progression. Therefore, since these various treatments do not address the underlying cause of organ fibrosis, a strategy is needed to treat or prevent the onset of fibrosis. It has been suggested that various compounds derived from plant extracts, mineral extracts, or other natural extracts can be used to counteract the accumulation of AGEs. However, although natural extracts can be potential sources of anti-glycation compounds, obtaining suitable extracts is a time-consuming and costly process. This is because plant extracts may contain many different compounds, some of which can have undesirable effects or even impair antiglycation activity. Furthermore, since plants must be cultivated under specific conditions to obtain optimal quality and quantity of antiglycation compounds, the concentration of each compound can vary significantly depending on cultivation conditions, season, and region. In addition, it should be noted that plant extracts are expensive to produce because a large amount of raw materials is required to obtain a sufficient amount of active compounds. In particular, some plants contain only small amounts of these compounds, which means that large quantities of plants must be harvested to obtain sufficient compounds for effective use. Partly due to this variability in the compounds present in plant extracts, it can be difficult to standardize formulations, reproduce results, and ensure consistent quality between batches. Furthermore, extracting desired compounds from plants is often a complex process. Specialized methods must be used to extract compounds in a manner that preserves their integrity and efficacy. This often requires expensive solvents and sophisticated equipment. Once the extract is obtained, it must be tested to ensure it contains the desired compounds