Broad-spectrum chemokine inhibitor

A broad-spectrum chemokine inhibitor or BSCI (also termed chemotide or somatotaxin ) is a type of experimental anti-inflammatory drug that inhibits the action of the pro-inflammatory proteins chemokines.[1] Radiolabeling experiments performed by Dr. David Fox, University of Warwick, demonstrated the ability of the BSCI to bind and antagonize the somatostatin receptor 2 (SSTR2). This is a display of functional selectivity at the SSTR2 receptor. Functional selectivity is the effect of one ligand having one agonism when bound to the receptor and another ligand having a different agonism at that same receptor.

Previous broad spectrum chemokine inhibitors.

Early peptides

The observation that the chemokine CCL2 is potentially responsible for the recruitment of macrophages to atherosclerotic lesions[2] initiated a campaign of research into the a class of molecules that would inhibit the trafficking of leukocytes and act as a new generation of anti-inflammatory agents. ‘Peptide 3’, a dodecapeptide section of CCL2, designed as an allosteric inhibitor of MCP-1 induced leukocyte chemotaxis, was quickly shown by leukocyte migration assay[3] to be a functional inhibitor of many chemokines in vitro with similar potency.[4] The potency of this peptide could be increased by cyclisation and the use of the reverse sequence of D-amino acids. This peptide is called NR58-3.14.3.[5][6]

In vivo anti-inflammatory activity

The cyclic peptide NR58-3.14.3 was shown to be a powerful anti-inflammatory agent in vivo,[7] inhibiting inflammation in a number of disease models such as atherosclerosis,[8] ischemia,[9][10][11] lung disease,[12] surgical adhesions,[13] endometriosis[14] and pulmonary graft-versus-host disease.[15] It has been suggested that blockage of chemokine function using these molecules should not have a detrimental toxicological effect.[16]

Anti-HIV activity

Cyclic peptide NR58-3.14.3 has also been shown to inhibit HIV replication.[17]

Preterm Labor

The BSCI compound called 'BN83470' in pregnant mice averted infection-induced preterm birth (PTB) by blocking various inflammatory pathways in the uterus and preventing the infiltration of immune cells into the uterine myometrium.[18] In a nonhuman primate model of Group B Streptococcus (GBS)-induced preterm labour, another BSCI compound called 'FX125L' was able to inhibit preterm labour and suppress the cytokine response.[19] No antibiotics were administered during these experiments, allowing the GBS infection to progress and invade the amniotic cavity and the fetus. Despite the invasive GBS infection, prophylactic BSCI treatment significantly reduced the levels of cytokines in the amniotic fluid, fetal plasma, lung, and brain, indicating its ability to suppress the inflammatory response. Current animal studies have not shown any significant fetal toxicity associated with BSCI compounds. However, further research, particularly through human pre-clinical trials, is now underway to understand the impact of BSCIs on the fetal immune response and development.[20][21][22]

Small molecule drug candidates

The key amino acids of the BSCI peptides required for activity have been identified, and the tripeptide AcNH-Trp-Val-Gln-OH was shown to itself be a BSCI in the low micromolar range. Based on this structure a number of peptide mimetics were designed, including a range of 3-acylaminoglutarimides, with low nanomolar BSCI potencies.[23] The search for increased stability and potency led to the development of 3-acylaminolactams,[24] with picomolar potencies in vitro and high anti-inflammatory activity in vivo.[25] A small molecule member of this class of BSCIs called FX125L, under development by Funxional Therapeutics, has recently completed phase 2 clinical trials.

References

  1. ^ Grainger DJ, Reckless J, Fox DJ (2005). "Broad Spectrum Chemokine Inhibitors Related to NR58-3.14.3". Mini-Rev. Med. Chem. 5 (9): 825–32. doi:10.2174/1389557054867101. PMID 16178724. Archived from the original on 2011-10-06.
  2. ^ Reckless J, Rubin EM, Verstuyft JB, Metcalfe JC, Grainger DJ (1999). "Monocyte Chemoattractant Protein-1 but Not Tumor Necrosis Factor-{alpha} Is Correlated With Monocyte Infiltration in Mouse Lipid Lesions". Circulation. 99 (17): 2310–6. doi:10.1161/01.cir.99.17.2310. PMID 10226098.
  3. ^ Frow EK, Reckless J, Grainger DJ (2004). "Tools for anti-inflammatory drug design: In vitro models of leukocyte migration". Med. Res. Rev. 24 (3): 276–98. doi:10.1002/med.10062. PMID 14994365. S2CID 42807089. Archived from the original on 2013-01-05.
  4. ^ 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.
  5. ^ Reckless J, Tatalick LM, Grainger DJ (2001). "The pan-chemokine inhibitor NR58-3.14.3 abolishes tumour necrosis factor-alpha 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.
  6. ^ Wilbert SM, Engrissei G, Yau EK, Grainger DJ, Tatalick L, Axworthy DB (2000). "Quantitative analysis of a synthetic peptide, NR58-3.14.3, in serum by LC-MS with inclusion of a diastereomer as internal standard". Anal. Biochem. 278 (1): 14–21. doi:10.1006/abio.1999.4437. PMID 10640348.
  7. ^ Grainger DJ, Reckless J (2003). "Broad-spectrum chemokine inhibitors (BSCIs) and their anti-inflammatory effects in vivo". Biochem. Pharmacol. 65 (7): 1027–34. doi:10.1016/S0006-2952(02)01626-X. PMID 12663038.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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. Retrieved 2009-04-10.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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. Retrieved 2019-06-16.
  17. ^ 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.
  18. ^ Shynlova, Oksana; Dorogin, Anna; Li, Yunqing; Lye, Stephen (September 2014). "Inhibition of infection‐mediated preterm birth by administration of broad spectrum chemokine inhibitor in mice". Journal of Cellular and Molecular Medicine. 18 (9): 1816–1829. doi:10.1111/jcmm.12307. ISSN 1582-1838. PMC 4196657. PMID 24894878.
  19. ^ Coleman, Michelle; Orvis, Austyn; Wu, Tsung-Yen; Dacanay, Matthew; Merillat, Sean; Ogle, Jason; Baldessari, Audrey; Kretzer, Nicole M.; Munson, Jeff; Boros-Rausch, Adam J.; Shynlova, Oksana; Lye, Stephen; Rajagopal, Lakshmi; Adams Waldorf, Kristina M. (2020). "A Broad Spectrum Chemokine Inhibitor Prevents Preterm Labor but Not Microbial Invasion of the Amniotic Cavity or Neonatal Morbidity in a Non-human Primate Model". Frontiers in Immunology. 11: 770. doi:10.3389/fimmu.2020.00770. ISSN 1664-3224. PMC 7203489. PMID 32425945.
  20. ^ Boros-Rausch, Adam; Shynlova, Oksana; Lye, Stephen James (January 2022). "A Broad-Spectrum Chemokine Inhibitor Blocks Inflammation-Induced Myometrial Myocyte–Macrophage Crosstalk and Myometrial Contraction". Cells. 11 (1): 128. doi:10.3390/cells11010128. ISSN 2073-4409. PMC 8750067. PMID 35011690.
  21. ^ Shynlova, Oksana; Boros-Rausch, Adam; Farine, Tali; Adams Waldorf, Kristina M.; Dunk, Caroline; Lye, Stephen J. (2021-10-15). "Decidual Inflammation Drives Chemokine-Mediated Immune Infiltration Contributing to Term Labor". The Journal of Immunology. 207 (8): 2015–2026. doi:10.4049/jimmunol.2100493. ISSN 0022-1767. PMC 8742659. PMID 34526377.
  22. ^ Coler, Brahm Seymour; Shynlova, Oksana; Boros-Rausch, Adam; Lye, Stephen; McCartney, Stephen; Leimert, Kelycia B.; Xu, Wendy; Chemtob, Sylvain; Olson, David; Li, Miranda; Huebner, Emily; Curtin, Anna; Kachikis, Alisa; Savitsky, Leah; Paul, Jonathan W. (2021-06-29). "Landscape of Preterm Birth Therapeutics and a Path Forward". Journal of Clinical Medicine. 10 (13): 2912. doi:10.3390/jcm10132912. ISSN 2077-0383. PMC 8268657. PMID 34209869.
  23. ^ Fox DJ, Reckless J, Warren SG, Grainger DJ (2002). "Design, Synthesis, and Preliminary Pharmacological Evaluation of N-Acyl-3-aminoglutarimides as Broad-Spectrum Chemokine Inhibitors in Vitro and Anti-inflammatory Agents in Vivo". J. Med. Chem. 45 (2): 360–70. doi:10.1021/jm010984i. PMID 11784140.
  24. ^ Fox DJ, Reckless J, Wilbert SM, Greig I, Warren SG, Grainger DJ (2005). "Identification of 3-(Acylamino)azepan-2-ones as Stable Broad-Spectrum Chemokine Inhibitors Resistant to Metabolism in Vivo". J. Med. Chem. 48 (3): 867–74. doi:10.1021/jm049365a. PMID 15689171.
  25. ^ Fox DJ, Reckless J, Lingard H, Warren S, Grainger DJ (2009). "Highly Potent, Orally Available Anti-inflammatory Broad-Spectrum Chemokine Inhibitors". J. Med. Chem. 52 (11): 3591–5. doi:10.1021/jm900133w. PMID 19425597.

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