Letermovir|917389-32-3|安捷凯

Background

AIC246, also known as letermovir, is a novel anti-CMV compound with IC50 value of 5.1 ± 1.2 nM. It targets the pUL56 (amino acid 230-370) subunit of the viral terminase complex [1].
The subunit pUL56 is a component of the terminase complex which is responsible for packaging unit length DNA into assembling virions.
AIC246 has a novel mode of action targets the enzyme UL56 terminase and keep active to other drug-resistant virus. The anti-HCMV activity of AIC246 was evaluated in vitro by using different HCMV laboratory strains, GCV-resistant viruses. The result showed that the inhibitory potentcy of AIC246 surpasses the current gold standard GCV by more than 400-fold with respect to EC50s (mean, ～4.5 nM versus ～2 μM) and by more than 2,000-fold with respect to EC90 values (mean, ～6.1 nM versus ～14.5 μM).? In the CPE-RA strains, the EC50 values of AIC 246 ranged from 1.8 nM to 6.1 nM [2].
In mouse model with HCMV subcutaneous xenograft, oral administration of AIC246 caused significant a dose-dependent reduction of the HCMV titer. 30 mg/kg/d AIC246 for 9 days induced PFU reduction with maximum efficiency, compared with the gold standard GCV at the ED50 and ED90 level [2].
参考文献:
[1].Verghese PS, Schleiss MR. Letermovir Treatment of Human Cytomegalovirus Infection Anti-infective Agent. Drugs Future. 2013, 38(5):291-298.
[2]. Lischka P1, Hewlett G, Wunberg T, et al.In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246.Antimicrob Agents Chemother. 2010, 54(3):1290-1297.

Protocol

Cell experiment:

Briefly, 5×103?AD169-infected NHDF cells/well are seeded into the wells of 30 96-well microtiter plates. The infection is allowed to proceed under the exposure of 50 nM AIC246 (10×EC50) until a CPE developed in one or more of the compound-treated wells (indicative of resistant virus breakthrough). Noninfected and nontreated cells serve as controls on each plate. Mutant virus amplification is accomplwashed after cultures achieved maximum CPE by the passage of cell-free supernatant virus in the presence of 50 nM AIC246. The resultant AIC246-resistant progeny virus mutants are plaque purified three times by limiting dilutions in the presence of AIC246. The stability of resistance is tested by serially passaging plaque-purified viruses without selective pressure (8 to 10 times).?

Animal experiment:

Mice (18 to 25 g body weight) are anesthetized, and the Gelfoam sponges are implanted subcutaneously in the dorsoscapular area. After transplantation, mice are randomized and grouped in 10 animals per treatment group. Starting 4 h after transplantation, mice are treated once daily with letermovir for nine consecutive days. Drugs are applied per os by oral gavage. Total administration volume is 10 mL/kg. Mice are sacrificed after 9 days of treatment, and the Gelfoam implants are removed and digested with collagenase at 37°C. After 2 to 3 h, human cells are recovered by centrifugation and resuspended in GM. Subsequently, the isolated cell suspensions are serially diluted and mixed with uninfected NHDF indicator cells and PFU are determined by plaque assays as described above. Virus titers determined from isolated cells are given as PFU/mL.

参考文献:

[1]. Marschall M, et al. In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses. Antimicrob Agents Chemother. 2012 Feb;56(2):1135-7.
[2]. Goldner T, et al. The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol. 2011 Oct;85(20):10884-93.
[3]. Lischka P, et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother. 2010 Mar;54(3):1290-7.
[4]. Wildum S, et al. In vitro drug combination studies of?Letermovir?(AIC246, MK-8228) with approved anti-human cytomegalovirus (HCMV) and anti-HIV compounds in inhibition of HCMV and HIV replication. Antimicrob Agents Chemother. 2015;59(6):3140-8.

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