GS-9620 (Vesatolimod) is a potent, orally active Toll-like receptor 7 (TLR7) agonist with an EC50 value of 291nM, exhibiting antiviral activity[1, 2]. TLR7 is a pathogen recognition receptor that plays a critical role in pathogen detection and in mediating innate immune responses against pathogens[3]. GS-9620 is capable of enhancing HIV-specific cytotoxicity and anti-HIV antibody-mediated immunity[4].
In vitro, treatment of peripheral blood mononuclear cells (PBMCs) with GS-9620 (10-1000nM) for 36h significantly increased cytokine levels in the culture supernatant; specifically, Interleukin-6 (IL-6) levels increased 218-fold, IFN-α increased 186-fold, and IFN-β increased 81-fold[5]. Treatment of FMDV-infected LFBK cells with GS-9620 (78-625μM) for 48 and 72h reduced intracellular viral copy numbers in a dose-dependent manner and elevated IFN-α levels in the cell supernatant[6].
In vivo, oral administration of GS-9620 (4.5mg/kg) three times to mice infected with the EV71 virus significantly alleviated clinical symptoms and improved survival rates. Furthermore, it significantly reduced serum levels of pro-inflammatory cytokines—such as IFN-α, IFN-γ, and MCP-1, and activated the NF-κB and PI3K/AKT signaling pathways within limb muscle cells[7].
References:
[1] Wang Y K, Wei L, Hu W, et al. Medicinal chemistry of anti-HIV-1 latency chemotherapeutics: biotargets, binding modes and structure-activity relationship investigation[J]. Molecules, 2022, 28(1): 3.
[2] Lopatin U, Wolfgang G, Tumas D, et al. Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like receptor 7 agonist[J]. Antiviral therapy, 2013, 18(3): 409-418.
[3] Kawai T, Akira S. Pathogen recognition with Toll-like receptors[J]. Current opinion in immunology, 2005, 17(4): 338-344.
[4] Tsai A, Irrinki A, Kaur J, et al. Toll-like receptor 7 agonist GS-9620 induces HIV expression and HIV-specific immunity in cells from HIV-infected individuals on suppressive antiretroviral therapy[J]. Journal of virology, 2017, 91(8): 10.1128/jvi. 02166-16.
[5] Bam R A, Hansen D, Irrinki A, et al. TLR7 agonist GS-9620 is a potent inhibitor of acute HIV-1 infection in human peripheral blood mononuclear cells[J]. Antimicrobial agents and chemotherapy, 2017, 61(1): 10.1128/aac. 01369-16.
[6] Lee G, Kang H R, Kim A, et al. Antiviral effect of vesatolimod (GS-9620) against foot-and-mouth disease virus both in vitro and in vivo[J]. Antiviral Research, 2022, 205: 105384.
[7] Zhang Q, Zhao B, Chen X, et al. GS-9620 inhibits enterovirus 71 replication mainly through the NF-κB and PI3K-AKT signaling pathways[J]. Antiviral Research, 2018, 153: 39-48.
GS-9620 (Vesatolimod)是一种具口服活性的有效的Toll样受体7（TLR7）激动剂，EC50值为291nM，具有抗病毒作用[1, 2]。TLR7是一种病原体识别受体，在检测病原体及对病原体的先天免疫反应中起着重要作用[3]。GS-9620能够增强HIV特异性细胞毒性和抗HIV抗体介导免疫[4]。
在体外，GS-9620（10-1000nM）处理外周血单核细胞（PBMCs）36h，显著增加了培养上清液中细胞因子水平，其中白细胞介素-6（IL-6）增加了218倍，IFN-α增加了186倍，IFN-β增加了81倍[5]。GS-9620（78-625μM）处理FMDV感染的LFBK细胞48h和72h，以剂量依赖性方式降低了细胞内病毒拷贝数，提高了细胞上清液中IFN-α水平[6]。
在体内，GS-9620（4.5mg/kg）通过口服治疗EV71病毒感染小鼠3次，显著缓解了小鼠的临床症状并提高了存活率，显著降低了血清中促炎细胞因子如 IFN-α、IFN-γ和MCP-1的水平，激活了肢体肌肉细胞中的NF-κB和PI3K/AKT信号通路[7]。