Mattos Mayara, Sacramento Carolina Q, Ferreira André C, Fintelman-Rodrigues Natalia, Pereira-Dutra Filipe S, de Freitas Caroline Souza, Gesto João S M, Temerozo Jairo R, Silva Aline de Paula Dias Da, Moreira Mariana T G, Silva Rafael S C, Silveira Gabriel P E, Pinto Douglas P, Pereira Heliana M, Fonseca Laís B, Alves Ferreira Marcelo, Blanco Camilla, Viola João P B, Bou-Habib Dumith Chequer, Bozza Patrícia T, Souza Thiago Moreno L
Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil.
National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-361, RJ, Brazil.
Viruses. 2024 Nov 29;16(12):1856. doi: 10.3390/v16121856.
Coronavirus disease 2019 (COVID-19) still causes death in elderly and immunocompromised individuals, for whom the sustainability of the vaccine response may be limited. Antiviral treatments, such as remdesivir or molnupiravir, have demonstrated limited clinical efficacy. Nirmatrelvir, an acute respiratory syndrome coronavirus 2 (SARS-CoV-2) major protease inhibitor, is clinically effective but has been associated with viral rebound and antiviral resistance. It is thus necessary to study novel and repurposed antivirals for the treatment of COVID-19. We previously demonstrated that daclatasvir (DCV), an inhibitor of the hepatitis C virus (HCV) NS5A protein, impairs SARS-CoV-2 replication by targeting viral RNA polymerase and exonuclease, but the doses of DCV used to inhibit the new coronavirus are greater than the standard human plasma exposure for hepatitis C. Because any potential use of DCV against SARS-CoV-2 would be shorter than that reported here and short-term toxicological studies on DCV show that higher doses are tolerable, we searched for doses of DCV that could protect transgenic mice expressing the human ACE2 receptor (K18-hACE-2) from lethal challenge with SARS-CoV-2. We found that a dose of 60 mg/kg/day provides this protection by reducing virus replication and virus-induced lung insult. This dose is tolerable in different animal models. Taken together, our data provide preclinical evidence that can support phase I clinical trials to confirm the safety, tolerability, and pharmacokinetics of new doses of daclatasvir for a short duration in humans to further advance this compound's utility against COVID-19.
2019冠状病毒病（COVID-19）仍会导致老年人和免疫功能低下者死亡，对他们而言，疫苗反应的可持续性可能有限。抗病毒治疗，如瑞德西韦或莫努匹韦，临床疗效有限。奈玛特韦是一种严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要蛋白酶抑制剂，临床有效，但与病毒反弹和抗病毒耐药性有关。因此，有必要研究新型和重新利用的抗病毒药物来治疗COVID-19。我们之前证明，丙型肝炎病毒（HCV）NS5A蛋白抑制剂达卡他韦（DCV）通过靶向病毒RNA聚合酶和核酸外切酶来损害SARS-CoV-2的复制，但用于抑制新型冠状病毒的DCV剂量高于丙型肝炎的标准人体血浆暴露量。由于DCV对SARS-CoV-2的任何潜在使用时间都将短于本文报道的时间，并且DCV的短期毒理学研究表明更高剂量是可耐受的，我们寻找能够保护表达人血管紧张素转换酶2受体（K18-hACE-2）的转基因小鼠免受SARS-CoV-2致死性攻击的DCV剂量。我们发现，60毫克/千克/天的剂量通过减少病毒复制和病毒诱导的肺部损伤提供了这种保护。该剂量在不同动物模型中是可耐受的。综上所述，我们的数据提供了临床前证据，可支持I期临床试验，以确认新剂量达卡他韦在人体内短时间的安全性、耐受性和药代动力学，从而进一步推进该化合物对COVID-19的治疗作用。
