Structure-based discovery of a specific TLR1–TLR2 small molecule agonist from the ZINC drug library database

Chen, Zhipeng; Cen, Xiaohong; Yang, Junjie; Tang, Xiaoshan; Cui, Kai; Cheng, Kui

doi:10.1039/c8cc06618c

Cited by 24 publications

(22 citation statements)

References 19 publications

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“…This compound has shown higher efficacy than the original compound and shows a specificity toward TLR-2/TLR-1 heterodimers over TLR-2/TLR-6 heterodimers (84). Using structure-based virtual screening of over 10.5 million compounds, Chen and colleagues identified ethyl 2-(4-methylpiperazine-1-carboxamido)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (SMU127) as a specific TLR-2/TLR-1 heterodimer ligand (85). Recently, the same group has developed 2-(1-(2-(Methylamino)-5-nitrophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)phenol (SMU-Z1) as a specific TLR-2/TLR-1 heterodimer ligand (86).…”

Section: Toll-like Receptorsmentioning

confidence: 99%

Targeting Cellular and Tissue HIV Reservoirs With Toll-Like Receptor Agonists

2019

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The elimination of both cellular and tissue latent reservoirs is a challenge toward a successful HIV cure. “Shock and Kill” are among the therapeutic strategies that have been more extensively studied to target these reservoirs. These strategies are aimed toward the reactivation of the latent reservoir using a latency-reversal agent (LRA) with the subsequent killing of the reactivated cell either by the cytotoxic arm of the immune system, including NK and CD8 T cells, or by viral cytopathic mechanisms. Numerous LRAs are currently being investigated in vitro, ex vivo as well as in vivo for their ability to reactivate and reduce latent reservoirs. Among those, several toll-like receptor (TLR) agonists have been shown to reactivate latent HIV. In humans, there are 10 TLRs that recognize different pathogen-associated molecular patterns. TLRs are present in several cell types, including CD4 T cells, the cell compartment that harbors the majority of the latent reservoir. Besides their ability to reactivate latent HIV, TLR agonists also increase immune activation and promote an antiviral response. These combined properties make TLR agonists unique among the different LRAs characterized to date. Additionally, some of these agonists have shown promise toward finding an HIV cure in animal models. When in combination with broadly neutralizing antibodies, TLR-7 agonists have shown to impact the SIV latent reservoir and delay viral rebound. Moreover, there are FDA-approved TLR agonists that are currently being investigated for cancer therapy and other diseases. All these has prompted clinical trials using TLR agonists either alone or in combination toward HIV eradication approaches. In this review, we provide an extensive characterization of the state-of-the-art of the use of TLR agonists toward HIV eradication strategies and the mechanism behind how TLR agonists target both cellular and tissue HIV reservoirs.

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Section: Toll-like Receptorsmentioning

confidence: 99%

Targeting Cellular and Tissue HIV Reservoirs With Toll-Like Receptor Agonists

2019

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“…ii) There are at least 10 human homologous of TLRs present in murine macrophages, all sharing a ligand‐binding domain with a double‐horseshoe shape and hence it is difficult to search for specific compounds, especially for TLR2, which can heterodimerizes with TLR1 or TLR6. In order to address these issues, as well as to continue our research interests in finding TLR2 modulators, we screened a synthetic library of 14 000 compounds and a series of newly developed compounds for NF‐κB activation using HEK‐Blue hTLR2 cells. Now we identified, synthesized and developed a novel small molecule, SMU‐Z1, which can specifically activate TLR2.…”

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confidence: 99%

“…The proliferation of spleen cells potentially reflected an increase in B or T cells. In order to specifically clarify the proliferation of B cells and effector T cells in vivo, we used flow cytometry for analysis on two different days (days 5 and 7). CD19 + , CD3 + , CD4 + , CD8 + , and TLR2 + markers were used.…”

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confidence: 99%

“…CD19 + , CD3 + , CD4 + , CD8 + , and TLR2 + markers were used. C57 mice were immunized by intraperitoneal injection of SMU‐Z1 (0.1 mg per mice), Pam 3 CSK 4 (5 µg per mice) or PBS for 5 to 7 d. After sacrifice, the percentage of positive cells in spleen, i.e., CD19 + B cells, CD4 + and CD8 + T cells, were determined by flow cytometry. No significant difference between the control and treated mice was observed in B cell numbers (Figure C).…”

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confidence: 99%

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TLR1/2 Specific Small‐Molecule Agonist Suppresses Leukemia Cancer Cell Growth by Stimulating Cytotoxic T Lymphocytes

et al. 2019

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Toll‐like receptor 2 (TLR2) expressed on antigen presenting cells evokes a series of critical cytokines, which favor the development of tumor‐specific cytotoxic T lymphocytes (CTLs). Therefore, TLR2 represents an attractive cancer immunotherapeutic target. Here, a synthetic library of 14 000 compounds together with a series of newly developed compounds for NF‐κB activation using HEK‐Blue hTLR2 cells is initially screened. Following further screening in a variety of cells including HEK‐Blue hTLRs reporter cells, murine, and human macrophage cell lines, a potent small molecule agonist 23 (SMU‐Z1) is identified, which specifically activates TLR2 through its association with TLR1, with a EC 50 of 4.88 ± 0.79 × 10 −9 m . Toxicology studies, proinflammatory cytokines (e.g., TNF‐α, IL‐1β, IL‐6, and nitric oxide) and target‐protein based biophysical assays demonstrate the pharmacologically relevant characteristics of SMU‐Z1. In addition, SMU‐Z1 promotes murine splenocyte proliferation and upregulates the expression of CD8 + T cells, NK cells and DCs, which results in a significant antitumor effect in a murine leukemia model. Finally, the induced tumors in three out of seven mice disappear after administration of SMU‐Z1. Our studies thus identify a novel and potent TLR1/2 small molecule agonist, which displays promising immune adjuvant properties and antitumor immunity.

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“…77 SMU127 and Purpurogallin are two anti-cancer agents with favorable effects against breast cancer and leukemic cells that exerted their property through simultaneous stimulation of TLR1 and TLR2. 78…”

Section: Tlr1/2 Agonistsmentioning

confidence: 99%