CMX001

CMX001 is a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV) used for treatment of smallpox.^[1]

In vitro experiment it shown that 0.079 μM CMX001 inhibited JCV replication in COS-7 cells. And treatment with 0.038 μM or 0.6 μM CMX001 in PDA cells resulted in a obviously decreased the number of infectious JCV progeny in a concentration-dependent manner. Treatment with 0.079 to 10 μM CMX001 in COS-7 cells reduced the metabolic activity to 52% and BrdU incorporation to 10% at the highest concentration.^[2] CMX001 was active with EC90 of 0.31 μM at about 400-times-lower concentrations than the EC90 for CDV in the same test system.^[3] In vitro efficacy test it exhibited that treatment with 0.01 μM to 0.1 μM resulted in minimal cytotoxic effects in human fetal brain SVG cells.^[4] In vitro, CMX001 has against five variola virus strains with EC50 of averaged 0.11 μM.^[5]

In vivo clinical study it shown that treatment with oral CMX001 at a dose of 100 mg twice weekly obviously reduced the incidence of CMV events in recipients of hematopoietic-cell transplants.^[6] In ECTV-infected A/NCR mice, a 2.5 mg/kg dose of CMX001 given once daily for five days starting 4 h post-infection provides complete protection against a lethal intranasal challenge. Mice were treated with 10 mg/kg CMX001 when the fifth day, then followed by a 2.5 mg/kg dose every other day for 14 days can be completely protected from mortality. However, treatment with 20 mg/kg CMX001 orally as late as four days post-infection provided 100% protection against lethal ECTV infection.^[7]

References:

[1].Rice AD, et al. Efficacy of CMX001 as a post exposure antiviral in New Zealand White rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans. Viruses. 2011 Jan;3(1):47-62.

[2].Gosert R, et al. CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes. Antimicrob Agents Chemother. 2011 May;55(5):2129-36.

[3].Rinaldo CH, et al. 1-O-hexadecyloxypropyl cidofovir (CMX001) effectively inhibits polyomavirus BK replication in primary human renal tubular epithelial cells. Antimicrob Agents Chemother. 2010 Nov;54(11):4714-22.

[4].Jiang ZG, et al. Hexadecyloxypropyl-cidofovir (CMX001) suppresses JC virus replication in human fetal brain SVG cell cultures. Antimicrob Agents Chemother. 2010 Nov;54(11):4723-32.

[5].Olson VA, et al. In vitro efficacy of brincidofovir against variola virus. Antimicrob Agents Chemother. 2014 Sep;58(9):5570-1.

[6].Marty FM, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013 Sep 26;369(13):1227-36.

[7].Lanier R, et al. Development of CMX001 for the Treatment of Poxvirus Infections. Viruses. 2010 Dec;2(12):2740-2762.

CMX001 是一种亲脂性核苷酸类似物，由 3-(hexdecyloxy)propan-1-ol 与西多福韦 (CDV) 共价连接而成，用于治疗天花。^[1]

体外实验表明，0.079 μM CMX001 可抑制 COS-7 细胞中的 JCV 复制。在 PDA 细胞中用 0.038 μM 或 0.6 μM CMX001 处理导致感染性 JCV 后代数量明显减少，且呈浓度依赖性。在 COS-7 细胞中用 0.079 至 10 μM CMX001 处理，在最高浓度下，代谢活性降低至 52%，BrdU 掺入降低至 10%。^[2] CMX001 在大约 0.31 μM 时具有活性，EC90 为 0.31 μM在同一测试系统中，浓度比 CDV 的 EC90 低 400 倍。^[3] 体外药效测试表明，0.01 μM 至 0.1 μM 的处理对人胎儿大脑的细胞毒性作用最小SVG 细胞。^[4] 在体外，CMX001 对五种天花病毒株具有平均 EC50 0.11 μM。^[5]

体内临床研究表明，每周两次口服 CMX001 100 mg 可显着降低造血细胞移植受者的 CMV 事件发生率。^[6] 在 ECTV-对于感染的 A/NCR 小鼠，从感染后 4 小时开始每天一次给予 2.5 mg/kg 剂量的 CMX001，持续五天，可提供针对致命鼻内攻击的完全保护。小鼠在第五天时用 10 mg/kg CMX001 处理，然后每隔一天用 2.5 mg/kg 剂量处理，持续 14 天可以完全保护免于死亡。然而，最晚在感染后 4 天口服 20 mg/kg CMX001 可提供 100% 的保护，防止致命的 ECTV 感染。^[7]