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NR58-3.14.3

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NR58.3-14-3
Names
IUPAC name
(3S,6S,9S,12S,15R,18R,21R,26S,29R)-21-amino-3,9-bis(4-aminobutyl)-6,18-bis(3-amino-3-oxopropyl)-15-[(2S)-butan-2-yl]-32-(carboxymethyl)-12-(1H-indol-3-ylmethyl)-29-(2-methylpropyl)-2,5,8,11,14,17,20,28,31,34-decaoxo-23,24-dithia-1,4,7,10,13,16,19,27,30,33-decazabicyclo[33.3.0]octatriacontane-26-carboxylic acid
Identifiers
3D model (JSmol)
  • InChI=1S/C60H94N16O16S2/c1-5-32(4)49-58(89)73-42(26-33-28-66-36-14-7-6-13-34(33)36)55(86)68-37(15-8-10-22-61)51(82)69-38(18-20-46(64)77)52(83)70-40(16-9-11-23-62)59(90)76-24-12-17-45(76)57(88)72-43(27-48(79)80)56(87)71-41(25-31(2)3)54(85)74-44(60(91)92)30-94-93-29-35(63)50(81)67-39(53(84)75-49)19-21-47(65)78/h6-7,13-14,28,31-32,35,37-45,49,66H,5,8-12,15-27,29-30,61-63H2,1-4H3,(H2,64,77)(H2,65,78)(H,67,81)(H,68,86)(H,69,82)(H,70,83)(H,71,87)(H,72,88)(H,73,89)(H,74,85)(H,75,84)(H,79,80)(H,91,92)/t32-,35-,37-,38-,39+,40-,41+,42-,43?,44+,45?,49+/m0/s1
    Key: FBAWIVCCEBIKFB-QOQTVHDZSA-N
  • CC[C@H](C)[C@@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N2CCCC2C(=O)NC(C(=O)N[C@@H](C(=O)N[C@H](CSSC[C@@H](C(=O)N[C@@H](C(=O)N1)CCC(=O)N)N)C(=O)O)CC(C)C)CC(=O)O)CCCCN)CCC(=O)N)CCCCN)CC3=CNC4=CC=CC=C43
Properties
C60H94N16O16S2
Molar mass 1359.63 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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NR58.3-14-3 is a cyclic peptide consisting of 11 D-amino acids. It is a broad-spectrum chemokine inhibitor and anti-inflammatory agent.

Development from 'Peptide 3'

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'Peptide 3' is a 12-amino acid linear peptide corresponding to amino acids 51 to 62 of mature human chemokine CCL2. It is formed from L-amino acids with the sequence NH2-Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln-OH (or in single letter code NH2-EICADPKQKWVQ-OH). 'Peptide 3' was found to be a Broad-Spectrum Chemokine Inhibitor inhibiting chemotaxis of human myelomonocytic cell line THP-1 monocytes and human neutrophils induced by a range of chemokines including CCL2, CCL3, CXCL8 and CXCL12 with roughly equal potency of 10μM, but not migration induced by other non-chemokine chemoattractants such as n-formyl-Met-Leu-Phe (fMLP) or TGF-β. Biotinylated 'Peptide 3' was found to bind to THP-1 cells with a disassociation constant of roughly 10μM. This suggested that 'Peptide 3' functions as a chemokine receptor antagonist. This mechanism was later proved to not be in action.[1]

Structure-activity experiments

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When the 12-amino acid sequence of 'peptide 3'/CCL2 is aligned with the sequences of the other chemokines CCL3, CXCL8 and CXCL12 5 amino acids are conserved, Cys3, Asp5, Pro6, Trp10 and Gln12. In addition Val11 is also present in CCL3 and CXCL8. The corresponding 11th amino acid in CXCL12 is Ile. Ala4 in CCL2 is also present in CCL3 but the corresponding residue is Leu in CXCL8 and Ile in CXCL12. Inclusion of Leu at position 4 and Ile at position 11 (NH2-EICLDPKQKWIQ-OH) increased the inhibition potency of the peptide to 2-4μM.

Removal of the first two residues from 'Peptide 3' (NH2-CADPKQKWVQ-OH) does not lower its BSCI potency.

Peptide 3-Leu4, Ile11, the most potent BSCI peptide was chosen for further development.[2] The first two amino acids were removed, and then according to the method of Jameson et al.,[3] the amino acid sequence was reversed and the amino acids replaced with D-amino acids. This combined transformation changes the orientation of the amides in the backbone but does not change the position of the amino acid sidechains. The peptide was then cyclised by adding a cysteine to the other end (HO-CLDPKQKWIQC-NH2), and oxidisation to form a disulfide bond to give NR58,3-14-3.

In vitro activity

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Like 'Peptide 3', NR58,3-14-3 is a broad-spectrum chemokine inhibitor. It however significantly more active than its earlier analogues migration inhibition potencies of 2.5 to 25 nM vs. CCL2, CCL3, CCL5 and CXCL12 with THP-1 monocytes, and vs. CXCL8 with neutrophils. In addition NR58,3-14-3 does not significantly inhibit leukocyte migration due to the other non-chemokine chemoattractants fMLP and C5a.

In vivo activity

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NR58-3.14.3 also inhibits the recruitment of leukocytes (macrophages, T cells, B cells) due to the chemokine CCL2 in rat skin. A similar effect was observed using Lipopolysaccharide (LPS) instead of CCL2 (macrophages, neutrophils, T cells, B cells). In addition NR58-3.14.3 inhibits LPS-induced accumulation of tumour necrosis factor-α (TNF-α). This is consistent with the peptide acting as a chemokine inhibitor up-steam of TNF-α productsion and anti-inflammatory in vivo.

The cyclic peptide NR58-3.14.3 was shown to be a powerful anti-inflammatory agent in vivo inhibiting inflammation in a number of disease models such as atherosclerosis,[4] ischemia,[5][6][7] lung disease,[8] surgical adhesions,[9] endometriosis[10] and pulmonary graft-versus-host disease.[11] It has been suggested that blockage of chemokine function using these molecules should not have a detrimental toxicological effect.[12]

Anti-HIV activity

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Cyclic peptide NR58-3.14.3 has also been shown to inhibit HIV replication.[13]

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Other peptide sequences derived from MCP-1 have been shown to elicit and inhibit cell migration.[14][15]

References

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  1. ^ Reckless J, Grainger DJ (1999). "Identification of oligopeptide sequences which inhibit migration induced by a wide range of chemokines". Biochem. J. 340 (3): 803–11. doi:10.1042/0264-6021:3400803. PMC 1220314. PMID 10359667.
  2. ^ Reckless J, Tatalick LM, Grainger DJ (2001). "The pan-chemokine inhibitor NR58-3.14.3 abolishes tumour necrosis factor-α accumulation and leucocyte recruitment induced by lipopolysaccharide in vivo". Immunology. 103 (2): 244–54. doi:10.1046/j.1365-2567.2001.01228.x. PMC 1783230. PMID 11412312.
  3. ^ Jameson BA, McDonnell JM, Marini JC, Korngold R (1994). "A rationally designed CD4 analog inhibits experimental allergic encephalomyelitis". Nature. 368 (6473): 744–6. Bibcode:1994Natur.368..744J. doi:10.1038/368744a0. PMID 8152486. S2CID 4370797.
  4. ^ Reckless J, Tatalick L, Wilbert S, McKilligin E, Grainger DJ (2005). "Broad-spectrum chemokine inhibition reduces vascular macrophage accumulation and collagenolysis consistent with plaque stabilization in mice". J. Vasc. Res. 42 (6): 492–502. doi:10.1159/000088139. PMID 16155365. S2CID 27296569.
  5. ^ Beech JS, Reckless J, Mosedale DE, Grainger DJ, Williams SC, Menon DK (2001). "Neuroprotection in ischemia-reperfusion injury: an antiinflammatory approach using a novel broad-spectrum chemokine inhibitor". J. Cereb. Blood Flow Metab. 21 (6): 683–9. doi:10.1097/00004647-200106000-00006. PMID 11488537.
  6. ^ Naidu BV, Farivar AS, Woolley SM, Grainger D, Verrier ED, Mulligan MS (2004). "Novel broad-spectrum chemokine inhibitor protects against lung ischemia-reperfusion injury". J. Heart Lung Transplant. 23 (1): 128–34. doi:10.1016/S1053-2498(03)00102-5. PMID 14734138.
  7. ^ Beech JS, Wheeler DW, Reckless J, Grant AJ, Price J, Mastroeni P, Grainger DJ, Menon DK (2007). "The MHP36 line of murine neural stem cells expresses functional CXCR1 chemokine receptors that initiate chemotaxis in vitro". J. Neuroimmunol. 184 (1–2): 198–208. doi:10.1016/j.jneuroim.2006.12.015. PMID 17289163. S2CID 30795173.
  8. ^ Naidu BV, Farivar AS, Krishnadasan B, Woolley SM, Grainger DJ, Verrier ED, Mulligan MS (2003). "Broad-spectrum chemokine inhibition ameliorates experimental obliterative bronchiolitis". Ann. Thorac. Surg. 75 (4): 1118–22. doi:10.1016/S0003-4975(02)04758-6. PMID 12683548. Archived from the original on 2008-09-05.
  9. ^ Berkkanoglu M, Zhang L, Ulukus M, Cakmak H, Kayisli UA, Kursun S, Arici A (2005). "Inhibition of chemokines prevents intraperitoneal adhesions in mice". Hum. Reprod. 20 (11): 3047–52. doi:10.1093/humrep/dei182. PMID 16006464.
  10. ^ Kayisli UA, Berkkanoglu M, Zhang L, Kizilay G, Arici A (2007). "The Broad-Spectrum Chemokine Inhibitor NR58-3.14.3 Suppresses the Implantation and Survival of Human Endometrial Implants in the Nude Mice Endometriosis Model". Reprod. Sci. 14 (8): 825–35. doi:10.1177/1933719107305865. PMID 18089601. S2CID 27817908.
  11. ^ Miklos S, Mueller G, Chang Y, Bouazzaoui A, Spacenko E, Schubert TE, Grainger DJ, Holler E, Andreesen R, Hildebrandt GC (2009). "Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease". Int. J. Hematol. 89 (3): 383–97. doi:10.1007/s12185-009-0272-y. PMID 19288173. S2CID 44783662.
  12. ^ Schroff RW, Touvay C, Culler MD, Dong JZ, Taylor JE, Thurieau C, McKilligin E (2005). "The Toxicology of Chemokine Inhibition". Mini Rev. Med. Chem. 5 (9): 849–55. doi:10.2174/1389557054867093. PMID 16178726. Archived from the original on 2011-10-06.
  13. ^ Grainger DJ, Lever AM (2005). "Blockade of chemokine-induced signalling inhibits CCR5-dependent HIV infection in vitro without blocking gp120/CCR5 interaction". Retrovirology Med. Chem. 2 (1): 23. doi:10.1186/1742-4690-2-23. PMC 1082716. PMID 15807900.
  14. ^ M. V. Sidorova; A. S. Molokoedov; T. I. Aref’eva; N. B. Kukhtina; T. L. Krasnikova; Zh. D. Bespalova; V. N. Bushuev (2004). "Peptide Fragments and Structural Analogues of Chemokine MCP-1: Synthesis and Effect on the MCP-1-Induced Migration of Mononuclear Cells". Russ. J. Bioorg. Chem. 30 (6): 582–93. doi:10.1023/B:RUBI.0000049768.98894.f5. PMID 15586809. S2CID 34574526.
  15. ^ M. V. Sidorova; A. S. Molokoedov; A. A. Az’muko; T. I. Aref’eva; M. G. Melekhov; N. B. Kukhtina; T. L. Krasnikova; Zh. D. Bespalova & V. N. Bushuev (2006). "Peptide Fragment 66–77 of Monocyte Chemoattractant Protein 1 and Its retro-enantioAnalogue Inhibit the Migration of Cells In Vitro and In Vivo". Russ. J. Bioorg. Chem. 32 (2): 146. doi:10.1134/S1068162006020063. S2CID 12988413.
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