ATI-2341

Several examples of allosteric modulators of GPCRs have been reported recently in the literature, but understanding their molecular mechanism presents a new challenge for medicinal chemistry. For the specific case of the cellular receptor CXCR4, it is known that pepducins (lipidated fragments of intracellular GPCR loops) such as ATI-2341 modulate CXCR4 activity agonistically via an allosteric mechanism. Moreover, there are also examples of small organic molecules such as AMD11070 and GSK812397 which may also act as allosteric antagonists. However, incomplete knowledge of the ligand-binding sites has hampered a detailed molecular understanding of how these inhibitors work. Here, we attempt to answer this question by analysing the binding interactions between the CXCR4 receptor and the above-mentioned allosteric modulators. We propose two different allosteric binding sites, one located in the intracellular loops 1, 2 and 3 (ICL1, ICL2 and ICL3) which binds the pepducin agonist ATI-2341, and the other at a subsite of the main extracellular orthosteric binding pocket between extracellular loops 1 and 2 and the N-terminus, which binds the antagonists AMD11070 and GSK812397. Allosteric interactions between the CXCR4 and ATI-2341 were predicted by combining different modeling approaches. First, a rotational blind docking search was applied and the best poses were subsequently refined using flexible docking methods and molecular dynamic simulations. For the AMD11070 and GSK812397 antagonists, the entire CXCR4 protein surface was explored by blind docking in order to define the binding region. A second docking analysis by subsites was then performed to refine the allosteric interactions. Finally, we identified the binding residues that appear to be essential for CXCR4 allosteric modulators.

Introduction:Pharmacological mobilization has been exploited as a means to obtain hematopoietic stem progenitor cells (HSPCs) for hematopoietic reconstitution. HSPCs mobilized from bone marrow into peripheral blood (PB) are a preferred source of stem cells for transplantation, because they are easily accessible and evidence indicates that they engraft faster after transplantation than HSPCs directly harvested from bone marrow (BM) or umbilical cord blood (UCB).Areas covered:Since chemokine-chemokine receptor axes are involved in retention of HSPCs in the BM microenvironment, chemokine receptor agonists have been proposed as therapeutics to facilitate the mobilization process. These compounds include agonists of the CXCR4 receptor expressed on HSPCs (CTCE-0021 and ATI-2341) or chemokines binding to chemokine receptors expressed on granuclocytes and monocytes (e.g., CXCL2, also known as the growth-related oncogene protein-beta (Gro-β); CCL3, also known as macrophage inflammatory protein-1α (MIP-1α); or CXCL8, also known as IL-8) could be employed alone or in combination with other mobilizing agents (e.g., G-CSF or Plerixafor (AMD3100)). We discuss the current state of knowledge about chemokine receptor agonists and the rationale for their application in mobilization protocols.Expert opinion:Evidence is accumulating that CXCR4 receptor agonists could be employed alone or with other agents as mobilizing drugs. In particular they may provide an alternative for patients that are poor mobilizers.

Sigma non-opioid intracellular receptor 1 (Sigma-1R) has been proven to play a major role in inflammation and structural remodeling. However, its role in airway inflammation and airway remodeling remains unclear. The purpose of this study aimed to explore the role and mechanism of Sigma-1R in airway remodeling and epithelial-mesenchymal transition (EMT) process in vivo and in vitro. We observed the decrease of Sigma-1R in lung tissue of asthma model. In the mouse model of allergic airway inflammation (AAI), Sigma-1R agonist RPE-084 significantly relieved airway inflammation and airway remodeling, while Sigma-1R antagonist BD1047 (B8562) had opposite effects. Further research showed that RPE-084 treatment increased the expression of pAMPK and inhibited the expression of CXCR4. Furthermore, RPE-084 treatment suppressed the levels of IL-4, IL-5, and IL-13 in BALF. We found that RPE-084 or Sigma-1R overexpression vector treatment regulated cell cycle and inhibited cell proliferation, migration, and EMT process in TGF-β1-induced 16HBE cells. Finally, we confirmed that AMP-activated protein kinase (AMPK) inhibitor compound C or CXCR4 agonist ATI-2341 both reversed the effects of Sigma-1R on TGF-β1-induced 16 HBE cells. In a word, our research shows that Sigma-1R is helpful to improve airway remodeling of asthma, and emphasizes a new candidate molecular for asthma treatment.