Letermovir is an orally antiviral compound that inhibits the cytomegalovirus (CMV) DNA terminase, with an EC50 value of 4.0nM [1]. Letermovir inhibits the viral terminase complex at pUL56 and pUL51 resulting in the cleavage of viral genomic units and accumulation of immature viral DNA, thereby inhibiting CMV replication [2]. The effect of Letermovir is in the prevention of the cleavage of long DNA concatemers into individual viral subunits, thereby resulting in noninfectious long DNA particles [3]. Letermovir has been widely used to reduce the incidence of CMV infection during allogeneic hematopoietic stem cell transplantation[4].
In vitro, Letermovir treatment for 6 days at 24nM reduced the CMV (BADrUL131-Y) replication in ARPE-19 cells[5].
In vivo, Letermovir treatment via oral administration at a dose of 30mg/kg/day for 9 days led to a notable reduction of the CMV titer within transplanted NHDF cells infected with CMV in the mouse xenograft model [6].
References:
[1] Wildum S, Zimmermann H, Lischka P. 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[J]. Antimicrobial agents and chemotherapy, 2015, 59(6): 3140-3148..
[2] Marty F M, Ljungman P, Chemaly R F, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation[J]. New England Journal of Medicine, 2017, 377(25): 2433-2444.
[3] El Helou G, Razonable R R. Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review[J]. Infection and drug resistance, 2019: 1481-1491.
[4] Chemaly R F, Ullmann A J, Stoelben S, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation[J]. New England Journal of Medicine, 2014, 370(19): 1781-1789.
[5] Giménez E, Guerreiro M, Gozalbo-Rovira R, et al. In vitro assessment of the combined effect of letermovir and sirolimus on cytomegalovirus replication[J]. Revista Española de Quimioterapia, 2023, 36(5): 526.
[6] Lischka P, Hewlett G, Wunberg T, et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246[J]. Antimicrobial agents and chemotherapy, 2010, 54(3): 1290-1297.
Letermovir是一种口服抗病毒化合物，可抑制巨细胞病毒（CMV）DNA terminase，EC50值为4.0nM[1]。Letermovir抑制pUL56和pUL51位点的病毒终止酶复合物，导致病毒基因组单位切割受阻及未成熟病毒DNA积累，从而抑制CMV复制[2]。Letermovir的作用是阻止长DNA连环体切割成单个病毒亚单位，从而产生无感染性的长DNA颗粒[3]。Letermovir已被广泛用于降低异基因造血干细胞移植期间CMV感染的发生率[4]。
在体外，使用24nM的Letermovir处理6天，可减少ARPE-19细胞中CMV（BADrUL131-Y）的复制 [5]。
在体内，在移植了感染了CMV的NHDF细胞的小鼠异种移植模型中，每日口服30mg/kg剂量的Letermovir，持续9天，显著降低了CMV滴度[6]。