Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities

Zhang, Heng; Kang, Dongwei; Huang, Boshi; Liu, Na; Zhao, Fabao; Zhan, Peng; Liu, Xinyong

doi:10.1016/j.ejmech.2016.02.051

Cited by 29 publications

(19 citation statements)

References 60 publications

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“…Given the early discovery that chemokine receptor CXCR4 facilitates HIV-1 entry in CD4-positive T-lymphocytes, this receptor was initially studied as a candidate drug target for anti-HIV therapy [6, 14]. This led to the discovery of several CXCR4-targeting compounds capable of inhibiting HIV infection in CD4-positive T-lymphocytes, including the cyclams, polyphemusin II and analogs derived thereof.…”

Section: Discussionmentioning

confidence: 99%

“…g . T140, TC14012, AMD3465, AMD11070 and IT1t) [14, 21]. All of them are potent CXCR4 inhibitors of HIV-1 replication (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…Various CXCR4-targeting compounds, including anti-CXCR4 peptides, non-peptide small molecule antagonists, CXCL12 peptide analogs and anti-CXCR4 antibodies have so far been evaluated in in vitro experimental studies and pre-clinical animal models to investigate their effectiveness in inhibiting CXCR4 function [13, 14]. The variety of applied biological assays and experimental conditions, however, makes it difficult to truly compare their binding characteristics, relative potencies and mode of action (direct versus indirect mechanisms) which might hamper their use in novel disease models and further drug design.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of cell-based assays for the identification and evaluation of competitive CXCR4 inhibitors

et al. 2017

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The chemokine receptor CXCR4 is activated by its unique chemokine ligand CXCL12 and regulates many physiological and developmental processes such as hematopoietic cell trafficking. CXCR4 is also one of the main co-receptors for human immunodeficiency virus (HIV) entry. Dysfunction of the CXCL12/CXCR4 axis contributes to several human pathologies, including cancer and inflammatory diseases. Consequently, inhibition of CXCR4 activation is recognized as an attractive target for therapeutic intervention. In this regard, numerous agents modifying CXCR4 activity have been evaluated in in vitro experimental studies and pre-clinical models. Here, we evaluated a CXCL12 competition binding assay for its potential as a valuable initial screen for functional and competitive CXCR4 inhibitors. In total, 11 structurally diverse compounds were included in a side-by-side comparison of in vitro CXCR4 cell-based assays, such as CXCL12 competition binding, CXCL12-induced calcium signaling, CXCR4 internalization, CXCL12-guided cell migration and CXCR4-specific HIV-1 replication experiments. Our data indicated that agents that inhibit CXCL12 binding, i.e. the anti-CXCR4 peptide analogs T22, T140 and TC14012 and the small molecule antagonists AMD3100, AMD3465, AMD11070 and IT1t showed inhibitory activity with consistent relative potencies in all further applied CXCR4-related assays. Accordingly, agents exerting no or very weak receptor binding (i.e., CTCE-9908, WZ811, Me6TREN and gambogic acid) showed no or very poor anti-CXCR4 inhibitory activity. Thus, CXCL12 competition binding studies were proven to be highly valuable as an initial screening assay and indicative for the pharmacological and functional profile of competitive CXCR4 antagonists, which will help the design of new potent CXCR4 inhibitors.

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Section: Discussionmentioning

confidence: 99%

“…g . T140, TC14012, AMD3465, AMD11070 and IT1t) [14, 21]. All of them are potent CXCR4 inhibitors of HIV-1 replication (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of cell-based assays for the identification and evaluation of competitive CXCR4 inhibitors

et al. 2017

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“…The contribution of CXCR4 in the above‐mentioned pathologies makes this receptor an extremely attractive drug target. Over the last decades, several small potent CXCR4 inhibitors have been engineered to block HIV‐1 infection and metastasis development . However, until now only AMD3100 (Plerixafor or Mozobil) has been approved as a hematopoietic stem cell mobilizer for patients with non‐Hodgkin lymphoma and multiple myeloma .…”

Section: Introductionmentioning

confidence: 99%

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Fiévez

Szpakowska

Mosbah

et al. 2018

Journal of Leukocyte Biology

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The chemokine receptor CXCR4 (C-X-C chemokine receptor type 4 also known as fusin or CD184 (cluster of differentiation 184)) is implicated in various biological and pathological processes of the hematopoietic and immune systems. CXCR4 is also one of the major coreceptors for HIV-1 entry into target cells and is overexpressed in many cancers, supporting cell survival, proliferation, and migration. CXCR4 is thus an extremely relevant drug target. Among the different strategies to block CXCR4, chemokine-derived peptide inhibitors hold great therapeutic potential. In this study, we used the N-terminus of vCCL2/vMIPII, a viral CXCR4 antagonist chemokine, as a scaffold motif to engineer and select CXCR4 peptide inhibitors, called Mimokines, which imitate the chemokine-binding mode but display an enhanced receptor affinity, antiviral properties, and receptor selectivity. We first engineered a Mimokine phage displayed library based on the first 21 residues of vCCL2, in which cysteine 11 and 12 were fully randomized and screened it against purified CXCR4 stabilized in liposomes. We identified Mimokines displaying up to 4-fold higher affinity for CXCR4 when compared to the reference peptide and fully protected MT-4 cells against HIV-1 infection. These selected Mimokines were then subjected to dimerization, D-amino acid, and aza-β3-amino acid substitution to further enhance their potency and selectivity. Optimized Mimokines exhibited up to 120-fold enhanced CXCR4 binding (range of 20 nM) and more than 200-fold improved antiviral properties (≤ 1 μM) compared to the parental Mimokines. Interestingly, these optimized Mimokines also showed up to 25-fold weaker affinity for ACKR3/CXCR7 and may therefore serve as lead compounds for further development of more selective CXCR4 peptide inhibitors and probes.

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“…1), which was originally used for treatment of HIV[9]. However, AMD3100 was not approved for this purpose due to poor oral bioavailability and serious cardiotoxicity [10–13]. In particular, AMD3100, a complete CXCR4 inhibitor, acting as an effective stem cell mobilizer by dissociating CXCR4 from its ligand CXCL12, has been FDA-approved for the use in patients with multiple myeloma in order to mobilize and harvest stem cells [14, 15].…”

Section: Introductionmentioning

confidence: 99%

Novel anti-inflammatory agents targeting CXCR4: Design, synthesis, biological evaluation and preliminary pharmacokinetic study

Bai

Liang

Yoon

et al. 2017

European Journal of Medicinal Chemistry

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CXCR4 plays a crucial role in the inflammatory disease process, providing an attractive means for drug targeting. A series of novel amide-sulfamide derivatives were designed, synthesized and comprehensively evaluated. This new scaffold exhibited much more potent CXCR4 inhibitory activity, with more than 70% of the compounds showed notably better binding affinity than the reference drug AMD3100 in the binding assay. Additionally, in the Matrigel invasion assay, most of our compounds significantly blocked the tumor cell invasion, demonstrating superior efficacy compared to AMD3100. Furthermore, compound IIj blocked mice ear inflammation by 75% and attenuated ear edema and damage substantially in an in vivo model of inflammation. Western blot analyses revealed that CXCR4 modulator IIj significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, compound IIj had no observable cytotoxicity and displayed a favourable plasma stability in our preliminary pharmacokinetic study. The preliminary structure-activity relationships were also summarized. In short, this novel amide-sulfamide scaffold exhibited potent CXCR4 inhibitory activity both in vitro and in vivo. These results also confirmed that developing modulators targeting CXCR4 provides an exciting avenue for treatment of inflammation.

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Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities

Cited by 29 publications

References 60 publications

Comparison of cell-based assays for the identification and evaluation of competitive CXCR4 inhibitors

Comparison of cell-based assays for the identification and evaluation of competitive CXCR4 inhibitors

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Novel anti-inflammatory agents targeting CXCR4: Design, synthesis, biological evaluation and preliminary pharmacokinetic study

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