Background
TMC353121 is a RSV fusion inhibitor. It has been developed from the precursor molecule JNJ-2408068 using a molecular modelling approach. It maintains high activity (pEC50 9.9) and low cytotoxicity, while presenting a shorter retention time in the lung (lung t1/2 25 h). [1]
TMC353121 was found to inhibit RSV by preventing both virus cell fusion and syncytia formation by causing a local disturbance of the natural six-helix bundle conformation of RSV-F protein.
TMC353121 reduces viral load in therapeutic and prophylactic administration. TMC353121 has potent antiviral properties in vivo in a BALB/c mice model and protects against lung infection and virus-induced inflammation.[2]
TMC353121 had dose-dependent antiviral activity, which varied from 1log10 reduction of
peak viral load to complete inhibition of the RSV replication. TMC353121 (0.39 μg/mL) can completely inhibit the shedding of RSV. And a dose-dependent reduction of INFγ, IL6 and MIP1α was associated. TMC353121 administered as CI for 16 days was generally well-tolerated. [3]
参考文献:
1. Bonfanti JF, Meyer C, Doublet F et al.? Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121). J Med Chem. 2008; 51: 875–896.
2. Olszewska W1, Ispas G, Schnoeller C et al.? Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model. Eur Respir J. 2011 Aug;38(2):401-8.
3. Ispas G, Koul A, Verbeeck J et al.? Antiviral Activity of TMC353121, a Respiratory Syncytial Virus (RSV) Fusion Inhibitor, in a Non-Human Primate Model. PLoS One. 2015 May 26;10(5):e0126959.
Protocol
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Animal experiment:
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Rats[2] Sprague-Dawley and cotton rats are given a single-bolus dose of 10 mg/kg TMC353121 intravenously (i.v.). Blood samples are taken from the orbital venous plexus of three Sprague-Dawley rats at 15 min and 1, 8, and 24 h postdose and from six Sprague-Dawley rats and six cotton rats at 3 h postdose. Blood samples are centrifuged at 1,500× g for 10 min, and plasma is separated and frozen until bioanalysis. After blood sampling, the rats are exsanguinated from the vena femoralis under isoflurane-oxygen anesthesia. Then they are euthanized by CO2 asphyxiation, and the lungs are subjected to lavage once via a tracheal cannula with phosphate-buffered saline (PBS) containing 2% bovine serum albumin (BSA) at room temperature at a volume of 5 mL per Sprague-Dawley rat or 2.5 mL per cotton rat. After gentle injection of the lavage fluid into the lungs, the fluid is withdrawn for collection of the bronchoalveolar lavage fluid (BALF) and the lungs are dissected. BALF is collected in order to assess TMC353121 concentrations in the lung epithelial lining fluid (ELF) after correction for the dilution with lavage fluid. A single lavage with a short dwelling time is applied as previously recommended for better accuracy of the determination of ELF dilution. BSA is added to the lavage fluid in order to prevent the adsorption of TMC353121 to syringes or other containers. The BALF is centrifuged at 300× g for 10 min, and the supernatant is separated. BALF supernatant and lung tissue samples are then frozen until bioanalysis. BALF supernatant is referred as BALF throughout this paper. Mice[3] Inbred 8- to 12-week-old female BALB/c mice are used. TMC353121 is administered intravenously in saline at doses of 0.25-10 mg/kg, and at various times in relation to the RSV infection. Mice are infected with 2×106 plaque-forming unit (PFU) of plaque-purified human strain RSV A2 (100 μL intranasally). Individual body weight is used to monitor animal health and response to infection, and is recorded daily.
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参考文献:
[1]. Bonfanti JF, et al. Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121). J Med Chem. 2008 Feb 28;51(4):875-96.
[2]. Rouan MC, et al. Pharmacokinetics-pharmacodynamics of a respiratory syncytial virus fusion inhibitor in the cotton rat model. Antimicrob Agents Chemother. 2010 Nov;54(11):4534-9.
[3]. Olszewska W, et al. Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model. Eur Respir J. 2011 Aug;38(2):401-8.
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