Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo.

Autor: Kumar N; Cellular Virology Lab, Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali (IISER Mohali), Mohali, India., Taily IM; Department of Chemistry, Indian Institute of Technology Ropar (IIT Ropar), Rupnagar, Punjab, India., Singh C; Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR-IMTECH), Chandigarh, India., Kumar S; Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR-IMTECH), Chandigarh, India., Rajmani RS; Molecular Biophysics Unit, Indian Institute of Science, Bangalore (IISc), Bengaluru, India., Chakraborty D; Molecular Biophysics Unit, Indian Institute of Science, Bangalore (IISc), Bengaluru, India., Sharma A; Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR-IMTECH), Chandigarh, India., Singh P; Department of Chemistry, Indian Institute of Technology Ropar (IIT Ropar), Rupnagar, Punjab, India., Thakur KG; Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR-IMTECH), Chandigarh, India., Varadarajan R; Molecular Biophysics Unit, Indian Institute of Science, Bangalore (IISc), Bengaluru, India., Ringe RP; Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR-IMTECH), Chandigarh, India., Banerjee P; Department of Chemistry, Indian Institute of Technology Ropar (IIT Ropar), Rupnagar, Punjab, India., Banerjee I; Cellular Virology Lab, Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali (IISER Mohali), Mohali, India.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 May 01; Vol. 19 (5), pp. e1011358. Date of Electronic Publication: 2023 May 01 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011358
Abstrakt: Rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) poses enormous challenge in the development of broad-spectrum antivirals that are effective against the existing and emerging viral strains. Virus entry through endocytosis represents an attractive target for drug development, as inhibition of this early infection step should block downstream infection processes, and potentially inhibit viruses sharing the same entry route. In this study, we report the identification of 1,3-diphenylurea (DPU) derivatives (DPUDs) as a new class of endocytosis inhibitors, which broadly restricted entry and replication of several SARS-CoV-2 and IAV strains. Importantly, the DPUDs did not induce any significant cytotoxicity at concentrations effective against the viral infections. Examining the uptake of cargoes specific to different endocytic pathways, we found that DPUDs majorly affected clathrin-mediated endocytosis, which both SARS-CoV-2 and IAV utilize for cellular entry. In the DPUD-treated cells, although virus binding on the cell surface was unaffected, internalization of both the viruses was drastically reduced. Since compounds similar to the DPUDs were previously reported to transport anions including chloride (Cl-) across lipid membrane and since intracellular Cl- concentration plays a critical role in regulating vesicular trafficking, we hypothesized that the observed defect in endocytosis by the DPUDs could be due to altered Cl- gradient across the cell membrane. Using in vitro assays we demonstrated that the DPUDs transported Cl- into the cell and led to intracellular Cl- accumulation, which possibly affected the endocytic machinery by perturbing intracellular Cl- homeostasis. Finally, we tested the DPUDs in mice challenged with IAV and mouse-adapted SARS-CoV-2 (MA 10). Treatment of the infected mice with the DPUDs led to remarkable body weight recovery, improved survival and significantly reduced lung viral load, highlighting their potential for development as broad-spectrum antivirals.
Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: NK, IB, IMT, PB, CS, AS, RPR, KGT and PS hold a US patent application (Application No. 17/932,386) covering some aspects of this study.
(Copyright: © 2023 Kumar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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