Development of targeted nanoparticles loaded with antiviral drugs for SARS-CoV-2 inhibition.
Development of targeted nanoparticles loaded with antiviral drugs for SARS-CoV-2 inhibition.
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DOI：
10.1016/j.ejmech.2022.114121
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发表时间：
2022-03-05
影响因子：
6.7
通讯作者：
Sechi M
中科院分区：
文献类型：
--
作者：
Sanna V;Satta S;Hsiai T;Sechi M
最近，一种新型冠状病毒，称为严重急性呼吸道综合征冠状病毒2（SARS-CoV-2），引起了全球关注，是当前2019年大流行性传染性冠状病毒病（COVID-19）的病原体。疫苗等特定预防性治疗方法已被多个国家的监管机构授权使用，但迫切需要确定新的、安全的、有针对性的治疗方法作为COVID-19的暴露后治疗。在众多潜在的药理学靶点中，血管紧张素转换酶2（ACE 2）膜受体在病毒进入中起着至关重要的作用，是SARS-CoV-2抗病毒发现过程中有吸引力的干预机会。在这种情况下，我们设想通过将配体多价连接到掺入抗病毒治疗剂的纳米载体上来结合ACE 2，这将增加受体亲合力并赋予这些纳米载体对宿主细胞的特异性，特别是在肺道中，这是SARS-CoV-2的主要进入途径。在此，我们报告了新型聚合物纳米颗粒（NP）的设计和开发，密集接枝各种配体选择性结合ACE 2，作为创新的纳米载体靶向药物输送。我们首先评估了这些生物相容性靶向NP（TNP）对ACE 2配体结合的影响，并测量了它们与刺突蛋白（Lipo-S1）模型的竞争能力。接下来，我们测试了最有效的纳米原型TNP-1的有效性，TNP-1装载有模型抗SARS-CoV-2药物，如瑞德西韦（RDV），对SARS-CoV-2感染的Vero E6细胞的抗病毒活性。与相同浓度的RDV相比，RDV-TNP-1表现出显著提高的抗病毒效果。有趣的是，未装载的TNP（TNP-1 E）也表现出基础的抗病毒活性，这可能是由于与病毒颗粒对ACE 2结合位点的直接竞争机制。我们还测量了TNP-1 E对ACE 2蛋白的抗外肽酶活性。总的来说，这些见解保证了我们的纳米原型的深入临床前开发，例如作为潜在的可吸入药物载体，从临床转化的角度来看。
Recently, a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised global concerns, being the etiological agent of the current pandemic infectious coronavirus disease 2019 (COVID-19). Specific prophylactic treatments like vaccines, have been authorized for use by regulatory bodies in multiple countries, however there is an urgent need to identify new, safe, and targeted therapeutics as post-exposure therapy for COVID-19. Among a plethora of potential pharmacological targets, the angiotensin-converting enzyme 2 (ACE2) membrane receptor, which plays a crucial role in viral entry, is representing an attractive intervention opportunity for SARS-CoV-2 antiviral discovery process. In this scenario, we envisioned that binding to ACE2 by multivalent attachment of ligands to nanocarriers incorporating antiviral therapeutics, it would increase receptor avidity and impart specificity to these nanovectors for host cells, particularly in the pulmonary tract, which is the primary entry route for SARS-CoV-2. Herein, we report the design and development of novel polymeric nanoparticles (NP), densely grafted with various ligands to selectively bind to ACE2, as innovative nanovectors for targeted drug delivery. We first evaluated the impact of these biocompatible targeted NP (TNP) on ligand binding toward ACE2 and measured their competition ability vs a model of spike protein (Lipo-S1). Next, we tested the effectiveness of the most performing nanoprotopype, TNP-1, loaded with a model anti-SARS-CoV-2 drug such as remdesivir (RDV), on antiviral activity against SARS-CoV-2 infected Vero E6 cells. The RDV-TNP-1 exhibited a significantly improved antiviral effect compared to RDV at the same concentration. Interestingly, unloaded TNP (TNP-1E) also exhibited a basal antiviral activity, potentially due to a direct competitive mechanism with viral particles for the ACE2 binding site. We also measured the anti-exopeptidase activity of TNP-1E against ACE2 protein. Collectively, these insights warrant in-depth preclinical development for our nanoprototypes, for example as potential inhalable drug carriers, with the perspective of a clinical translation.
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影响因子：
6.7
作者：
Boraei, Ahmed T. A.;Singh, Pankaj K.;Satta, Sandro
通讯作者：
Satta, Sandro
DOI：
10.1056/nejmoa2116846
发表时间：
2022-01-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gottlieb RL;Vaca CE;Paredes R;Mera J;Webb BJ;Perez G;Oguchi G;Ryan P;Nielsen BU;Brown M;Hidalgo A;Sachdeva Y;Mittal S;Osiyemi O;Skarbinski J;Juneja K;Hyland RH;Osinusi A;Chen S;Camus G;Abdelghany M;Davies S;Behenna-Renton N;Duff F;Marty FM;Katz MJ;Ginde AA;Brown SM;Schiffer JT;Hill JA;GS-US-540-9012 (PINETREE) Investigators
通讯作者：
GS-US-540-9012 (PINETREE) Investigators
影响因子：
2.9
作者：
Guy, JL;Jackson, RM;Turner, AJ
通讯作者：
Turner, AJ
影响因子：
28.3
作者：
Gorbalenya, Alexander E.;Baker, Susan C.;Ziebuhr, John
通讯作者：
Ziebuhr, John
影响因子：
15
作者：
Dales, NA;Gould, AE;Patane, MA
通讯作者：
Patane, MA