Chemistry:Broad-spectrum chemokine inhibitor

From HandWiki
Short description: Drug class

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. ↑ "Broad Spectrum Chemokine Inhibitors Related to NR58-3.14.3". Mini-Rev. Med. Chem. 5 (9): 825–32. 2005. doi:10.2174/1389557054867101. PMID 16178724. Archived from the original on 2011-10-06. https://web.archive.org/web/20111006101959/http://www.benthamdirect.org/pages/content.php?MRMC%2F2005%2F00000005%2F00000009%2F0005N.SGM. 
  2. ↑ "Monocyte Chemoattractant Protein-1 but Not Tumor Necrosis Factor-{alpha} Is Correlated With Monocyte Infiltration in Mouse Lipid Lesions". Circulation 99 (17): 2310–6. 1999. doi:10.1161/01.cir.99.17.2310. PMID 10226098. http://circ.ahajournals.org/cgi/content/abstract/99/17/2310. 
  3. ↑ "Tools for anti-inflammatory drug design: In vitro models of leukocyte migration". Med. Res. Rev. 24 (3): 276–98. 2004. doi:10.1002/med.10062. PMID 14994365. http://www3.interscience.wiley.com/journal/107612924/abstract. 
  4. ↑ "Identification of oligopeptide sequences which inhibit migration induced by a wide range of chemokines". Biochem. J. 340 (3): 803–11. 1999. doi:10.1042/0264-6021:3400803. PMID 10359667. 
  5. ↑ "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. 2001. doi:10.1046/j.1365-2567.2001.01228.x. PMID 11412312. 
  6. ↑ "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. 2000. doi:10.1006/abio.1999.4437. PMID 10640348. 
  7. ↑ "Broad-spectrum chemokine inhibitors (BSCIs) and their anti-inflammatory effects in vivo". Biochem. Pharmacol. 65 (7): 1027–34. 2003. doi:10.1016/S0006-2952(02)01626-X. PMID 12663038. 
  8. ↑ "Broad-spectrum chemokine inhibition reduces vascular macrophage accumulation and collagenolysis consistent with plaque stabilization in mice". J. Vasc. Res. 42 (6): 492–502. 2005. doi:10.1159/000088139. PMID 16155365. 
  9. ↑ "Neuroprotection in ischemia-reperfusion injury: an antiinflammatory approach using a novel broad-spectrum chemokine inhibitor". J. Cereb. Blood Flow Metab. 21 (6): 683–9. 2001. doi:10.1097/00004647-200106000-00006. PMID 11488537. 
  10. ↑ "Novel broad-spectrum chemokine inhibitor protects against lung ischemia-reperfusion injury". J. Heart Lung Transplant. 23 (1): 128–34. 2004. doi:10.1016/S1053-2498(03)00102-5. PMID 14734138. 
  11. ↑ "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. 2007. doi:10.1016/j.jneuroim.2006.12.015. PMID 17289163. http://www.jni-journal.com/article/S0165-5728(06)00521-2/abstract. 
  12. ↑ "Broad-spectrum chemokine inhibition ameliorates experimental obliterative bronchiolitis". Ann. Thorac. Surg. 75 (4): 1118–22. 2003. doi:10.1016/S0003-4975(02)04758-6. PMID 12683548. http://ats.ctsnetjournals.org/cgi/content/abstract/75/4/1118. Retrieved 2009-04-10. 
  13. ↑ "Inhibition of chemokines prevents intraperitoneal adhesions in mice". Hum. Reprod. 20 (11): 3047–52. 2005. doi:10.1093/humrep/dei182. PMID 16006464. 
  14. ↑ "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. 2007. doi:10.1177/1933719107305865. PMID 18089601. 
  15. ↑ "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. 2009. doi:10.1007/s12185-009-0272-y. PMID 19288173. 
  16. ↑ "The Toxicology of Chemokine Inhibition". Mini Rev. Med. Chem. 5 (9): 849–55. 2005. doi:10.2174/1389557054867093. PMID 16178726. http://www.benthamdirect.org/pages/content.php?MRMC/2005/00000005/00000009/0007N.SGM. Retrieved 2019-06-16. 
  17. ↑ "Blockade of chemokine-induced signalling inhibits CCR5-dependent HIV infection in vitro without blocking gp120/CCR5 interaction". Retrovirology Med. Chem. 2 (1): 23. 2005. doi:10.1186/1742-4690-2-23. 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" (in en). Journal of Cellular and Molecular Medicine 18 (9): 1816–1829. doi:10.1111/jcmm.12307. ISSN 1582-1838. PMID 24894878. 
  19. ↑ Coleman, Michelle; Orvis, Austyn; Wu, Tsung-Yen; Dacanay, Matthew; Merillat, Sean; Ogle, Jason; Baldessari, Audrey; Kretzer, Nicole M. et al. (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. 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" (in en). Cells 11 (1): 128. doi:10.3390/cells11010128. ISSN 2073-4409. 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" (in en). The Journal of Immunology 207 (8): 2015–2026. doi:10.4049/jimmunol.2100493. ISSN 0022-1767. PMID 34526377. PMC 8742659. https://journals.aai.org/jimmunol/article/207/8/2015/234627/Decidual-Inflammation-Drives-Chemokine-Mediated. 
  22. ↑ Coler, Brahm Seymour; Shynlova, Oksana; Boros-Rausch, Adam; Lye, Stephen; McCartney, Stephen; Leimert, Kelycia B.; Xu, Wendy; Chemtob, Sylvain et al. (2021-06-29). "Landscape of Preterm Birth Therapeutics and a Path Forward" (in en). Journal of Clinical Medicine 10 (13): 2912. doi:10.3390/jcm10132912. ISSN 2077-0383. PMID 34209869. 
  23. ↑ "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. 2002. doi:10.1021/jm010984i. PMID 11784140. 
  24. ↑ "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. 2005. doi:10.1021/jm049365a. PMID 15689171. 
  25. ↑ "Highly Potent, Orally Available Anti-inflammatory Broad-Spectrum Chemokine Inhibitors". J. Med. Chem. 52 (11): 3591–5. 2009. doi:10.1021/jm900133w. PMID 19425597. 

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Broad-spectrum_chemokine_inhibitor&oldid=3337426"