Department of Medical Biotechnologies, University of Siena, Siena, Italy.
Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124, Parma, Italy.
Eur J Med Chem. 2021 Nov 15;224:113683. doi: 10.1016/j.ejmech.2021.113683. Epub 2021 Jul 5.
The worldwide circulation of different viruses coupled with the increased frequency and diversity of new outbreaks, strongly highlight the need for new antiviral drugs to quickly react against potential pandemic pathogens. Broad-spectrum antiviral agents (BSAAs) represent the ideal option for a prompt response against multiple viruses, new and re-emerging. Starting from previously identified anti-flavivirus hits, we report herein the identification of promising BSAAs by submitting the multi-target 2,6-diaminopurine chemotype to a system-oriented optimization based on phenotypic screening on cell cultures infected with different viruses. Among the synthesized compounds, 6i showed low micromolar potency against Dengue, Zika, West Nile and Influenza A viruses (IC = 0.5-5.3 μM) with high selectivity index. Interestingly, 6i also inhibited SARS-CoV-2 replication in different cell lines, with higher potency on Calu-3 cells that better mimic the SARS-CoV-2 infection in vivo (IC = 0.5 μM, SI = 240). The multi-target effect of 6i on flavivirus replication was also analyzed in whole cell studies (in vitro selection and immunofluorescence) and against isolated host/viral targets.
不同病毒在全球范围内的传播，加上新疫情爆发的频率和多样性不断增加，强烈凸显了需要新的抗病毒药物来快速应对潜在的大流行病原体。广谱抗病毒药物 (BSAA) 是针对多种新出现和重新出现的病毒快速反应的理想选择。我们从先前鉴定的抗黄病毒命中出发，通过对感染不同病毒的细胞培养物进行表型筛选，将多靶点 2,6-二氨基嘌呤化学型提交给基于系统的优化，从而鉴定出有前途的广谱抗病毒药物。在所合成的化合物中，化合物 6i 对登革热、寨卡、西尼罗河和流感 A 病毒具有低微摩尔效力（IC = 0.5-5.3 μM），选择性指数高。有趣的是，化合物 6i 还抑制了不同细胞系中的 SARS-CoV-2 复制，在更能模拟体内 SARS-CoV-2 感染的 Calu-3 细胞中具有更高的效力（IC = 0.5 μM，SI = 240）。6i 对黄病毒复制的多靶点作用也在全细胞研究（体外选择和免疫荧光）和针对分离的宿主/病毒靶点中进行了分析。
