SMM-Chemokines: A Class of Unnatural Synthetic Molecules as Chemical Probes of Chemokine Receptor Biology and Leads for Therapeutic Development

Abstract

Chemokines and their receptors play important roles in numerous physiological and pathological processes. To develop natural chemokines into receptor probes and inhibitors of pathological processes, the lack of chemokine-receptor selectivity must be overcome. Here, we apply chemical synthesis and the concept of modular modifications to generate unnatural synthetically and modularly modified (SMM)-chemokines that have high receptor selectivity and affinity, and reduced toxicity. A proof of the concept was shown by transforming the nonselective viral macrophage inflammatory protein-II into new analogs with enhanced selectivity and potency for CXCR4 or CCR5, two principal coreceptors for human immunodeficiency virus (HIV)-1 entry. These new analogs provided insights into receptor binding and signaling mechanisms and acted as potent HIV-1 inhibitors. These results support the concept of SMM-chemokines for studying and controlling the function of other chemokine receptors.

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

“…These drugs presumably inhibit the neurotoxic effect of gp120 IIIB , at least in part, in a direct manner, as the CXCR4-specific SMM-chemokines and gp120 IIIB all interact with CXCR4. Furthermore, none of these CXCR4-selective SMMchemokines produced neurotoxicity on their own, which is consistent with our toxicity data on these compounds using human white blood cells (23). Taken together, our data indicate that inhibition of CXCR4 is an effective way of protecting neurons from gp120 IIIB -induced neurotoxicity, providing that the inhibitors used for blocking gp120 IIIB -CXCR4 interaction are not inherently neurotoxic like SDF-1␣ or vMIP-II.…”

“…N-(9-fluorenyl)methoxycarbonyl chemistry was employed for the synthesis (23,24). 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 1-hydroxybenzotriazole (HOBt) were used as coupling reagents in the presence of diisopropylethylamine (DIEA).…”

“…As such, we have been working toward the development of a family of unnatural chemokines, termed SMM-chemokines, which have higher receptor selectivity, binding affinity, and/or antiviral activities than natural chemokines. We previously demonstrated how this SMM-chemokine approach could be applied to convert the nonselective vMIP-II into highly selective ligands of CXCR4 or CCR5 in terms of their binding, signaling, and/or antiviral activity (23). We also used a similar strategy to modify the biological and pharmacological properties of SDF-1␣ (24).…”

“…By following a modified procedure published by others, including our own laboratory (1,9,19,23,25,33), the cultures were exposed to gp120 (400 pm), SMM-chemokines (20 nM), the Ser/Thr kinase Akt inhibitor (LY294002, 50 M), extracellular regulated kinase (ERK) inhibitor (PD98059, 2 M), c-JUN N-terminal kinase (JNK) inhibitor (SP600125, 10 M), p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580, 10 M), or combinations thereof for 24 h. SMMchemokines were applied for 5 min and intracellular signaling cascade inhibitors for 15 min prior to gp120 exposure. HIV-1/gp120 from X4-tropic strain IIIB was purchased from ImmunoDiagnostics (Woburn, MA); gp120 from the CCR5-preferring strain BAL was obtained through the AIDS Research and Reference Reagent program (Division of AIDS, NIAID, National Institutes of Health, Bethesda, MD).…”

Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias

“…This pattern of RCP168 binding disrupts HIV infection much more potently than SDF-1a signaling through CXCR4 (nanomolar versus micromolar concentrations), albeit both effects are mediated by modulating the function of this receptor (29). RCP112 is an analogue of viral macrophage inflammatory protein II in which the first 10 amino acids in the NH 2 terminus have been deleted; it has shown a significantly reduced affinity to CXCR4 (30). DVIP is a 21 D-amino acid peptide of NH 2 terminus viral macrophage inflammatory protein II with a higher biological stability (31).…”