白蛋白
血液蛋白质类
口粘液
蛋白酶
血浆蛋白结合
糖蛋白
化学
药代动力学
结合位点
分子生物学
呼吸系统
生物化学
生物
药理学
酶
内科学
医学
作者
Siennah R. Greenfield,Heather Eng,Qingyi Yang,Chunyang Guo,Laura J. Byrnes,Alyssa Dantonio,Graham M. West,Li Di,Amit S. Kalgutkar
出处
期刊:Xenobiotica
[Informa]
日期:2023-01-02
卷期号:53 (1): 12-24
被引量:3
标识
DOI:10.1080/00498254.2023.2183158
摘要
Plasma protein binding (PPB) studies on the SARS-CoV-2 main protease inhibitor nirmatrelvir revealed considerable species differences primarily in dog and rabbit, which prompted further investigations into the biochemical basis for these differences.The unbound fraction (fu) of nirmatrelvir in dog and rabbit plasma was concentration (2–200 µM)-dependent (dog fu,p 0.024–0.69, rabbit fu,p 0.010–0.82). Concentration (0.1–100 µM)-dependent binding in serum albumin (SA) (fu,SA 0.040–0.82) and alpha-1-acid glycoprotein (AAG) (fu,AAG 0.050–0.64) was observed in dogs. Nirmatrelvir showed minimal binding to rabbit SA (1–100 µM: fu,SA 0.70–0.79), while binding to rabbit AAG was concentration-dependent (0.1–100 µM: fu,AAG 0.024–0.66). In contrast, nirmatrelvir (2 µM) revealed minimal binding (fu,AAG 0.79–0.88) to AAG from rat and monkeys. Nirmatrelvir showed minimal-to-moderate binding to SA (1–100 µM; fu,SA 0.70–1.0) and AAG (0.1–100 µM; fu,AAG 0.48–0.58) from humans across tested concentrations.Nirmatrelvir molecular docking studies using published crystal structures and homology models of human and preclinical species SA and AAG were used to rationalise the species differences to plasma proteins. This suggested that species differences in PPB are primarily driven by molecular differences in albumin and AAG resulting in differences in binding affinity.
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