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.
The observation that the chemokineCCL2 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 leukocytemigration 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]
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]
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.
^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. PMID10640348.
^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. PMID12663038.
^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. PMID16155365. S2CID27296569.
^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. PMID18089601. S2CID27817908.
^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. PMID19288173. S2CID44783662.
^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. PMID11784140.
^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. PMID15689171.
^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. PMID19425597.