Design, synthesis, and biological characterization of a new class of symmetrical polyamine-based small molecule CXCR4 antagonists

Xiong, Fang; Meng, Qingqi; Zhang, Huijun; Liang, Boqiang; Zhu, Siyu; Wang, Juan; Zhang, Chaozai; Huang, Lina; Zhang, Xingquan; Schooley, Robert T.; An, Jing; Xu, Yixin; Huang, Ziwei

doi:10.1016/j.ejmech.2020.112410

Cited by 11 publications

(3 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The procedure for the CXCR4 competitive binding experiments was published previously [ 27 , 73 ]. Briefly, CXCR4 antibody 12G5 (250 ng/ml) was incubated with 5 × 10 5 cells and varying concentrations of unlabeled compounds in a final volume of 100 μl of assay buffer (PBS with 0.5% BSA and 0.05% NaN 3 ) in 96-well plates for 40 min on ice, after being washed with assay buffer once.…”

Section: Methodsmentioning

confidence: 99%

Biological and mutational analyses of CXCR4–antagonist interactions and design of new antagonistic analogs

Meng,

Zhu,

Mao

et al. 2023

Bioscience Reports

Self Cite

View full text Add to dashboard Cite

The chemokine receptor CXCR4 has become an attractive therapeutic target for HIV-1 infection, hematopoietic stem cell mobilization, and cancer metastasis. A wide variety of synthetic antagonists of CXCR4 have been developed and studied for a growing list of clinical applications. To compare the biological effects of different antagonists on CXCR4 functions and their common and/or distinctive molecular interactions with the receptor, we conducted head-to-head comparative cell-based biological and mutational analyses of the interactions with CXCR4 of eleven reported antagonists, including HC4319, DV3, DV1, DV1 dimer, V1, vMIP-II, CVX15, LY2510924, IT1t, AMD3100, and AMD11070 that were representative of different structural classes of D-peptides, L-peptide, natural chemokine, cyclic peptides, and small molecules. The results were rationalized by molecular modeling of CXCR4–antagonist interactions from which the common as well as different receptor binding sites of these antagonists were derived, revealing a number of important residues such as W94, D97, H113, D171, D262, and E288, mostly of negative charge. To further examine this finding, we designed and synthesized new antagonistic analogs by adding positively charged residues Arg to a D-peptide template to enhance the postulated charge–charge interactions. The newly designed analogs displayed significantly increased binding to CXCR4, which supports the notion that negatively charged residues of CXCR4 can engage in interactions with moieties of positive charge of the antagonistic ligands. The results from these mutational, modeling and new analog design studies shed new insight into the molecular mechanisms of different types of antagonists in recognizing CXCR4 and guide the development of new therapeutic agents.

show abstract

Section: Methodsmentioning

confidence: 99%

Biological and mutational analyses of CXCR4–antagonist interactions and design of new antagonistic analogs

Meng,

Zhu,

Mao

et al. 2023

Bioscience Reports

Self Cite

View full text Add to dashboard Cite

show abstract

“…Through our extensive research efforts over many years, we have developed a new class of small molecule agents that are potent antagonists of CXCR4. On the basis of our representative compound HF50731 [28], we have developed a new highly potent small molecule analog named HF51116, which features an unsymmetrical polyamine ( Fig. 1a).…”

Section: Mobilization Of Different Peripheral Blood Cells In Micementioning

confidence: 99%

A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. This retention depends on the interaction between the CXC chemokine receptor 4 (CXCR4) expressed on the HSCs and its natural chemokine ligand, stromal cell-derived factor (SDF)-1α (also named CXCL12) present in the BM stromal microenvironment. In clinical practice, blocking this interaction with a CXCR4 antagonist can induce the rapid mobilization of HSCs from the BM into the PB. Methods C3H/HEJ, DBA/2, CD45.1+, and CD45.2+ mice and monkeys were employed in colony-forming unit (CFU) assays, flow cytometry assays, and competitive/noncompetitive transplantation assays, to assess the short-term mobilization efficacy of HF51116 and the long-term repopulating (LTR) ability of HSCs. Kinetics of different blood cells and the concentration of HF51116 in PB were also explored by blood routine examinations and pharmacokinetic assays. Results In this paper, we report that a novel small molecule CXCR4 antagonist, HF51116, which was designed and synthesized by our laboratory, can rapidly and potently mobilize HSCs from BM to PB in mice and monkeys. HF51116 not only mobilized HSCs when used alone but also synergized with the mobilizing effects of granulocyte colony-stimulating factor (G-CSF) after co-administration. Following mobilization by HF51116 and G-CSF, the long-term repopulating (LTR) and self-renewing HSCs were sufficiently engrafted in primary and secondary lethally irradiated mice and were able to rescue and support long-term mouse survival. In monkeys, HF51116 exhibited strong HSC mobilization activity and quickly reached the highest in vivo blood drug concentration. Conclusions These results demonstrate that HF51116 is a new promising stem cell mobilizer which specifically targets CXCR4 and merits further preclinical and clinical studies.

show abstract

“…Extensive research is available related to the receptor of SDF-1, the CXCR4 chemokine receptor, and HIV-1. A search in PubMed on SDF-1 and HIV-1 leads to ∼500 articles and 40 reviews, the most recent (review) in May 2020 (31). The number of articles for HIV-1 and CXCR4 are ∼8 times higher, and the last review appeared in May 2020 (25).…”

Section: Ras Gpcrs the Blind Point In Sars Researchmentioning

confidence: 99%

SARS-CoV-2 as a Factor to Disbalance the Renin–Angiotensin System: A Suspect in the Case of Exacerbated IL-6 Production

Franco

Rivas‐Santisteban

Serrano-Marín

et al. 2020

The Journal of Immunology

View full text Add to dashboard Cite

Fever in infections correlates with inflammation, macrophage infiltration into the affected organ, macrophage activation, and release of cytokines involved in immune response, hematopoiesis, and homeostatic processes. Angiotensin-converting enzyme 2 (ACE2) is the canonical cell surface receptor for SARS-CoV-2. ACE2 together with angiotensin receptor types 1 and 2 and ACE2 are components of the renin–angiotensin system (RAS). Exacerbated production of cytokines, mainly IL-6, points to macrophages as key to understand differential COVID-19 severity. SARS-CoV-2 may modulate macrophage-mediated inflammation events by altering the balance between angiotensin II, which activates angiotensin receptor types 1 and 2, and angiotensin 1–7 and alamandine, which activate MAS proto-oncogene and MAS-related D receptors, respectively. In addition to macrophages, lung cells express RAS components; also, some lung cells are able to produce IL-6. Addressing how SARS-CoV-2 unbalances RAS functionality via ACE2 will help design therapies to attenuate a COVID-19–related cytokine storm.

show abstract

Design, synthesis, and biological characterization of a new class of symmetrical polyamine-based small molecule CXCR4 antagonists

Cited by 11 publications

References 52 publications

Biological and mutational analyses of CXCR4–antagonist interactions and design of new antagonistic analogs

Biological and mutational analyses of CXCR4–antagonist interactions and design of new antagonistic analogs

A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys

SARS-CoV-2 as a Factor to Disbalance the Renin–Angiotensin System: A Suspect in the Case of Exacerbated IL-6 Production

Contact Info

Product

Resources

About