Pharmaceutical Research Division, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
Research Area for Drug Candidate Generation II, Shionogi TechnoAdvance Research Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
J Antimicrob Chemother. 2023 Apr 3;78(4):946-952. doi: 10.1093/jac/dkad027.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become established in the human population, making the need to develop safe and effective treatments critical. We have developed the small-molecule antiviral ensitrelvir, which targets the 3C-like (3CL) protease of SARS-CoV-2. This study evaluated the in vitro and in vivo efficacy of ensitrelvir compared with that of another SARS-CoV-2 3CL PI, nirmatrelvir.
Cultured cells, BALB/cAJcl mice and Syrian hamsters were infected with various SARS-CoV-2 strains, including the ancestral strain WK-521, mouse-adapted SARS-CoV-2 (MA-P10) strain, Delta strain and Omicron strain. Ensitrelvir efficacy was compared with that of nirmatrelvir. Effective concentrations were determined in vitro based on virus-induced cytopathic effects, viral titres and RNA levels. Lung viral titres, nasal turbinate titres, body-weight changes, and animal survival were also monitored.
Ensitrelvir and nirmatrelvir showed comparable antiviral activity in multiple cell lines. Both ensitrelvir and nirmatrelvir reduced virus levels in the lungs of mice and the nasal turbinates and lungs of hamsters. However, ensitrelvir demonstrated comparable or better in vivo efficacy than that of nirmatrelvir when present at similar or slightly lower unbound-drug plasma concentrations.
Direct in vitro and in vivo efficacy comparisons of 3CL PIs revealed that ensitrelvir demonstrated comparable in vitro efficacy to that of nirmatrelvir in cell culture and exhibited equal to or greater in vivo efficacy in terms of unbound-drug plasma concentration in both animal models evaluated. The results suggest that ensitrelvir may become an important resource for treating individuals infected with SARS-CoV-2.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）已在人群中立足，因此开发安全有效的治疗方法至关重要。我们开发了靶向 SARS-CoV-2 的 3C 样（3CL）蛋白酶的小分子抗病毒药物 ensitrelvir。本研究评估了 ensitrelvir 与另一种 SARS-CoV-2 3CL PI（nirmatrelvir）在体外和体内的疗效。
用各种 SARS-CoV-2 株（包括原始株 WK-521、鼠适应株 SARS-CoV-2（MA-P10）株、Delta 株和奥密克戎株）感染培养细胞、BALB/cAJcl 小鼠和叙利亚仓鼠。比较 ensitrelvir 和 nirmatrelvir 的疗效。根据病毒诱导的细胞病变效应、病毒滴度和 RNA 水平，在体外确定有效浓度。还监测肺病毒滴度、鼻甲骨滴度、体重变化和动物存活率。
ensitrelvir 和 nirmatrelvir 在多种细胞系中显示出相当的抗病毒活性。ensitrelvir 和 nirmatrelvir 均降低了小鼠肺和鼻腔中的病毒水平，以及仓鼠的鼻腔和肺中的病毒水平。然而，当以相似或略低的未结合药物血浆浓度存在时，ensitrelvir 的体内疗效与 nirmatrelvir 相当或优于 nirmatrelvir。
3CL PI 的直接体外和体内疗效比较表明，ensitrelvir 在细胞培养中显示出与 nirmatrelvir 相当的体外疗效，并在两种评估的动物模型中以未结合药物血浆浓度表示，具有相等或更大的体内疗效。结果表明，ensitrelvir 可能成为治疗感染 SARS-CoV-2 的个体的重要资源。
