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Alpha type conotoxin peptide derivates and use thereof

A technology of peptide derivatives and conch, applied in the field of α-type conch polypeptide derivatives, can solve the problems of toxicity and side effect tolerance, poor treatment effect, etc., achieve strong analgesic activity, increase anti-enzymatic hydrolysis ability, folding Efficient effect

Inactive Publication Date: 2009-03-11
INST OF BIOENG ACAD OF MILITARY MEDICAL SCI OF THE CHINESE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinically commonly used drugs mainly include the combination of anticonvulsants (such as leticitide and oxcarbazepine), opioids (such as morphine) and various antidepressants. Receptivity, addiction and other problems, the treatment effect is not good (Dray et al, Br J Anaesth.2008, 101(1), 48-58; Gilron et al, Expert Opin Emerg Drugs.2007, 12(1), 113 -26.)

Method used

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  • Alpha type conotoxin peptide derivates and use thereof
  • Alpha type conotoxin peptide derivates and use thereof
  • Alpha type conotoxin peptide derivates and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Synthesis and purification of embodiment 1, HS-2

[0030] 1. Solid phase synthesis of HS-2

[0031] A series of α-type conopeptide derivatives were designed and synthesized, and the specific sequences are shown in Table 1.

[0032] Table 1 Sequences of α-type conus polypeptides and their derivatives

[0033]

[0034] In Table 1, A is alanine, E is glutamic acid, D is aspartic acid, C is cysteine, G is glycine, I is isoleucine, K is lysine, L is leucine Amino acid, N is asparagine, Q is glutamine, R is arginine, S is serine, V is valine, Y is tyrosine. The disulfide bond connection mode is C1-C3, C2-C4. * Indicates amidation (CONH 2 ).

[0035] The following takes HS-2 as an example to illustrate its preparation process.

[0036] 1. Synthesis of peptide resin

[0037] The synthesis of HS-2 was carried out on the 433A peptide synthesizer (ABI America Applied Systems Biological Instruments), the synthesis used solid-phase synthesis technology, and the amino acids...

Embodiment 2

[0080] Example 2: Screening α-type conus polypeptide derivatives with high analgesic activity using rat sciatic nerve hemisection model

[0081] 1. Build a model

[0082] SD rats, ♂, weighing 200-220 g, were provided by the Experimental Animal Center of the Academy of Military Medical Sciences of the Chinese People's Liberation Army.

[0083] A sciatic nerve hemisection model rat was constructed with reference to the literature (Seltzer et al. Pain, A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. 1990, 43, 205-218.). Under anesthesia and aseptic operation, the right sciatic nerve was exposed at the high position of the femur. Under a magnifying glass of 25 times, the dorsal side of the nerve was carefully separated from the surrounding tissue at the distal end of the branch of the sciatic nerve trunk to the posterior biceps and semitendinosus muscles. Separate it, clamp the dorsal side of the nerve with small hemostatic...

Embodiment 3

[0089] The dose-dependent experiment of embodiment 3, HS-2 and HS-10 analgesic effect

[0090] Seven days after the operation, the rats successfully modeled in the above-mentioned Example 2 were intramuscularly injected with the α-type conus polypeptide derivatives HS-2, HS-10 and Vc1.1 obtained in the above-mentioned Example 1. They were divided into three groups according to different injection doses: 3nmol group, 0.3nmol group and 0.06nmol group, with 6 rats in each group. At the same time, physiological saline was used as a negative control. After three consecutive days of administration, 2.5-3 hours after the third administration, the changes in the pain threshold of rats before and after administration were tested. The experiment was repeated three times, and the experimental results of the relationship between the analgesic activity and dose of HS-2 and HS-10 were as follows: Figure 4 shown. Figure 4 Among them, the ordinate is the increase rate of the pain thresho...

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Abstract

The invention discloses an alpha conus polypeptide derivative, amino acid residues of which are shown in sequence 1 in a sequence table. To effectively resist the degradation digestion of partial protease in a human body, and improve the bioavailability and the drug metabolism performance, an N end of the alpha conus polypeptide derivative can be connected with a benzoyl group. The alpha conus polypeptide derivative can also be subjected to cyclization, fattening or PEG modification to strengthen the treatment effect of the alpha conus polypeptide derivative. A big mouse experiment shows that the alpha conus polypeptide derivative shows strong analgesic activity in a neuropathic pain model of a big mouse, and the analgesic activity is remarkably higher than that of control peptide Vc1.1 and shows dose-dependent relation.

Description

technical field [0001] The present invention relates to α-type conus polypeptide derivatives and applications thereof. Background technique [0002] Cono snail polypeptides are a class of pharmacologically active polypeptides secreted by cono venom glands, generally composed of 9 to 40 amino acids, rich in cysteine, with small molecular weight, stable structure, high activity, high selectivity and easy synthesis. features. Conopeptides can specifically act on various receptor subtypes of neurotransmitters such as acetylcholine, as well as various ion channels such as calcium, sodium and potassium, and can not only be directly used as a drug, but also be used as an ideal molecular model for the development of new drugs lead compound. Among them, the omega-type cone snail polypeptide MVIIA has been approved by the FDA to enter the market as a drug for the treatment of HIV and advanced cancer pain; 3 It also has strong analgesic activity (Dai qy et al. J Nat Prod 2003, 66(9)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08A61K38/10A61P25/04
Inventor 戴秋云徐宁胡洁刘珠果
Owner INST OF BIOENG ACAD OF MILITARY MEDICAL SCI OF THE CHINESE
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