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Peptides modulating caspase activation

An active site, antibody technology, applied in the field of apoptotic cell death peptides, can solve the problem of not finding the special effect of CRGDVLDCL

Inactive Publication Date: 2005-11-30
鲍里斯·爱德华多维奇·塔图洛夫
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no specific effect of CRGDVLDCL was found, and the present invention is still the first to identify a putative bioactive site in AFP

Method used

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  • Peptides modulating caspase activation
  • Peptides modulating caspase activation
  • Peptides modulating caspase activation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] peptide synthesis

[0037] Peptides were synthesized using a Synthesizer Model 430A; Applied Biosystems, Foster City, CA, USA, according to common methods for peptide synthesis. Cyclic peptides are mainly formed spontaneously from linear peptides in aqueous solution exposed to atmospheric oxygen and are purified by HPLC, using usual procedures for peptides.

[0038] 1. Cyclic polymeric 9-peptide corresponding to amino acid sequence 251-259 in human AFP * Cys- * Cys-Arg-Gly-Asp-Val-Leu-Asp-Cys * , * CCRGDVLDC * (asterisks indicate potential disulfide bonds), referred to herein as apocyclin-A. The second cysteine, Cys252, is capable of forming an S-S bond between two adjacent cyclic monomeric peptides. The molecular weight of the monomeric cyclic peptide is 983 Da. The apocyclin-A peptide consists of two or more (less than 5) loops corresponding to the sequence * Cys- * Cys-Arg-Gly-Asp-Val-Leu-Asp-Cys * The 9-peptide structure composition.

[0039]

[0040] ...

Embodiment 2

[0057] Example 2 Identification of the RGD-containing caspase-3-specific active site responsible for apoptotic signaling in human AFP

[0058] To determine the functionally important amino acids in the AFP molecule, we determined the amino acid homology of the sequences of human AFP and caspase-3 to caspase-1 and constructed peptide analogs of putative active sites. Align the following sequences:

[0059] casp-2 QNKPKMFFI QUR ETDRGV

[0060] :::::

[0061] casp-1 KDKPKVIII QUR SPGVVW

[0062] :::::

[0063] casp-3 TGKPKLFII QACRGTE LDC GI

[0064] :::. :::

[0065] HuAFP VLDVAHVHEH CCRGDVLDC LQDGEKIMSYICSQQDTLSNKITECCKLTTLERGQCIIHAE 299

[0066] : :. :: :: ::.: : : . ::: .::..::. ::: ::. :: :

[0067] HSA VTDLTKVHTE CCHGDLLEC ADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVE 294

[0068] It can be seen from the comparison that AFP and caspase-1 have certain homology with the enzyme active sites of caspase-3. T...

Embodiment 3

[0069] Example 3 Cyclic peptide from AFP apocyclin-A eliminates AFP-induced apoptosis in U937 cells

[0070] Previously published data demonstrated that AFP of different origins (embryonic or derived from the culture medium of the hepatoma cell line HepG2) could induce growth inhibition and dose-dependent programmed cell death in various tumor cell lines, characterized by a typical Apoptotic features such as marked growth inhibition, cytotoxicity and DNA fragmentation (Dudich et al., (1998) Tumor Biol. 19:30-40). To determine the possible localization of the active site on the AFP molecule responsible for apoptotic signaling, we tested the ability of each AFP-derived peptide to block this effect. figure 2 It shows that AFP-derived peptide apocyclin-A completely eliminates AFP-induced apoptosis in U-937 cells. In addition, 15-minute pretreatment of U-937 cells with apocyclin-A (1 mM) induced a 15% stimulation of proliferation compared to medium control. This means that apocy...

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Abstract

The present invention provides structures of small molecules capable of modulating apoptotic cell death. More specifically, the structures relate to the structures of apoptotic active sites of mammalian alpha-fetoprotein (AFP) and albumin. Peptides mimicking the active site contain two sequences, Arg-Gly-Asp and Asp-X-X-Asp, wherein X means any amino acid. These sequences are needed in the same molecule for causing a wide range of biological activities. The peptides can be utilized to suppress apoptotic pathways by inhibiting the cytochrome c-mediated caspaseactivation. Thus, the peptides can be used to inhibit effects of apoptosis induced by oxidative stress, drugs, cytokines, Fas-ligand, alpha-fetoprotein, used to prevent apoptosis in culturing cells, in organ transplantation, in immunological autoimmune disorders and immunodeficiency syndrom induced by viral infection, or to diminish side cytotoxic effects after chemotherapy and radiation therapy.

Description

field of invention [0001] The present invention relates to drugs and mechanisms of human and animal cell death. Specifically, it relates to peptides capable of inhibiting apoptotic cell death caused by various factors. Peptides having such activity and methods of making and using the peptides are described. Background of the invention [0002] Apoptosis is an efficient form of cell death involved in normal cell development and transformation of malignant cells. Apoptotic mechanisms involve biological events caused by various types of drugs, cytokines and growth factors, oxygen stress, radiation, aging, autoimmune diseases and immune rejection in organ transplantation. Recent studies on apoptosis have shown that various types of apoptosis induced by hormones, cytokines, growth factor deficiency, chemotherapeutic drugs, ionizing radiation, immune disorders, AIDS, cancer and aging employ a common molecular mechanism (Nagata, (1997) Cell 88, 355-365). [0003] Cascade activa...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61P37/00C07K7/06C07K16/18C12N5/07C12N5/071C12N5/078C12N5/0793
CPCC07K7/06C07K16/18A61K39/00C07K2317/73A61P31/12A61P31/18A61P35/00A61P37/00A61P37/02A61P43/00
Inventor 埃琳娜·伊万诺夫娜·杜迪奇利迪娅·尼古拉耶芙娜·谢缅科夫安伊戈尔·维亚切斯拉沃维奇·杜迪奇爱德华·鲍里索维奇·塔图洛夫德米特里·利沃维奇·祖博夫蒂莫·卡莱维·科尔佩拉
Owner 鲍里斯·爱德华多维奇·塔图洛夫
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