AiCuris Anti-Infective Cures AG, 42117 Wuppertal, Germany.
J Med Chem. 2022 Oct 27;65(20):13614-13628. doi: 10.1021/acs.jmedchem.2c00668. Epub 2022 Oct 6.
When the nucleoside analogue acyclovir was introduced in the early 1980s, it presented a game-changing treatment modality for herpes simplex virus infections. Since then, work has been ongoing to improve the weaknesses that have now been identified: a narrow time window for therapeutic success, resistance in immunocompromised patients, little influence on frequency of recurrences, relatively fast elimination, and poor bioavailability. The present Drug Annotation focuses on the helicase-primase inhibitor pritelivir currently in development for the treatment of acyclovir-resistant HSV infections and describes how a change of the molecular target (from viral DNA polymerase to the HSV helicase-primase complex) afforded improvement of the shortcomings of nucleoside analogs. Details are presented for the discovery process leading to the final drug candidate, the pivotal preclinical studies on mechanism of action and efficacy, and on how ongoing clinical research has been able to translate preclinical promises into clinical use.
当核苷类似物阿昔洛韦在 20 世纪 80 年代初问世时，它为单纯疱疹病毒感染提供了一种改变游戏规则的治疗模式。从那时起，人们一直在努力改进现已确定的弱点：治疗成功的时间窗口狭窄、免疫功能低下患者的耐药性、对复发频率影响不大、消除速度相对较快以及生物利用度差。本药物注释重点介绍目前正在开发用于治疗阿昔洛韦耐药性 HSV 感染的解旋酶-引物酶抑制剂普立万，描述了改变分子靶标（从病毒 DNA 聚合酶到 HSV 解旋酶-引物酶复合物）如何改善核苷类似物的缺点。介绍了导致最终药物候选物的发现过程、作用机制和疗效的关键临床前研究，以及正在进行的临床研究如何将临床前的承诺转化为临床应用。
