生物活性

• 描述Toll like receptors are a membrane-based family which could modulate the immune responses by detecting distinct pathogen-associated molecular patterns on infectious agents^[7]. GS-9620 is an orally bioavailable small-molecule TLR7 agonist with EC50 value of 130 nM and 4,000 nM for TLR7 and TLR8, respectively^[8]. On the PBMCs from ART-suppressed HIV infected patients, the GS-9620 was added to the cells at 100 and 1000 nM and incubated for four days. The HIV RNA level in the cell culture supernatants was 1.7-1.9-fold increased after the treatment of GS-9620 compared with vehicle control. After two days of GS-9620 treatment on PBMCs, the IFN-α level as well as some proinflammatory cytokines and chemokines such as MCP-1, I-TAC, IL-1RA, IL-6, IL-10, MIP-1β, IP-10, and MIP-1α increased significantly as measured by multiplex immunoassays in the cell culture supernatant^[9]. GS-9620 was administered to chimpanzees with chronic HBV infection every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1 week rest, for 4 weeks at 2 mg/kg. The HBV DNA in serum and liver determined by qRCR declined gradually after the treatment. The administration of GS-9620 also induced production of IFN-α and other cytokines and chemokines, and activated ISGs, natural killer cells, and lymphocyte subsets measured by ELISA and flow cytometry^[10].
• 作用机制The GS-9620 can bind to the TLR7 in a pH responsive manner. The binding pocket of the GS-9620 may be formed by amino acids D555 and D557 in LRR17 region from one monomer and amino acids Y356 in LRR11 domain and F408 in LRR13 domain from the second monomer together^[11].

• 动物研究
  剂量	Chimpanzee: 0.3 mg/kg, 1 mg/kg[4] (p.o.) Woodchuck: 1 mg/kg -10 mg/kg[6] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01590654	Hepatitis B	Phase 1	Completed	-	-
  NCT03060447	HIV-1 Infection	Phase 1	Active, not recruiting	July 2020	United States, California ... more >> Mills Clinical Research Los Angeles, California, United States, 90069 Zuckerberg San Francisco General San Francisco, California, United States, 94110 United States, Florida Midway Immunology & Research Center Fort Pierce, Florida, United States, 34982 Orlando Immunology Center Orlando, Florida, United States, 32803 United States, Texas Central Texas Clinical Research Austin, Texas, United States, 78705 United States, Washington Peter Shalit, MD Seattle, Washington, United States, 98104 Collapse <<
  NCT02258581	-	-	Terminated	-	-

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• 参考文献

• [1] The GS-9620 can bind to the TLR7 in a pH responsive manner. The binding pocket of the GS-9620 may be formed by amino acids D555 and D557 in LRR17 region from one monomer and amino acids Y356 in LRR11 domain and F408 in LRR13 domain from the second monomer together[5].

  [2] Bam RA, Hansen D, et al. TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells. Antimicrob Agents Chemother. 2017;61(1).

  [3] Tsai A, Irrinki A, 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 Virol. 2017;91(8).

  [4] Lanford RE, Guerra B, et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology. 2013;144(7):1508-17, 1517.e1-10.

  [5] Rebbapragada I, Birkus G, et al. Molecular Determinants of GS-9620-Dependent TLR7 Activation. PLoS One. 2016;11(1):e0146835.

  [6] Menne S, Tumas DB, et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J Hepatol. 2015 Jun;62(6):1237-45.

  [7] Gordon S. Pattern recognition receptors: doubling up for the innate immune response. Cell. 2002 Dec 27;111(7):927-30.

  [8] Bam RA, Hansen D, Irrinki A, Mulato A, Jones GS, Hesselgesser J, Frey CR, Cihlar T, Yant SR. TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells. Antimicrob Agents Chemother. 2016 Dec 27;61(1):e01369-16.

  [9] Tsai A, Irrinki A, Kaur J, Cihlar T, Kukolj G, Sloan DD, Murry JP. 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 Virol. 2017 Mar 29;91(8):e02166-16.

  [10] Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM, Fosdick A, Frey CR, Zheng J, Wolfgang G, Halcomb RL, Tumas DB. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology. 2013 Jun;144(7):1508-17, 1517.e1-10.

  [11] Rebbapragada I, Birkus G, Perry J, Xing W, Kwon H, Pflanz S. Molecular Determinants of GS-9620-Dependent TLR7 Activation. PLoS One. 2016 Jan 19;11(1):e0146835.

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