Kumar, N and Taily, IM and Singh, C and Kumar, S and Rajmani, RS and Chakraborty, D and Sharma, A and Singh, P and Thakur, KG and Varadarajan, R and Ringe, RP and Banerjee, P and Banerjee, I (2023) Identification of diphenylurea derivatives as novel endocytosis inIdentification 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 vivohibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo. In: PLoS Pathogens, 19 (5).
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Abstract
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-diphe-nylurea (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 SARSCoV-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.
| Item Type: | Journal Article |
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| Publication: | PLoS Pathogens |
| Publisher: | Public Library of Science |
| Additional Information: | The copyright for this article belongs to the authors. |
| Keywords: | antivirus agent, animal; chemistry; coronavirus disease 2019; endocytosis; Influenza A virus; mouse; physiology; Severe acute respiratory syndrome coronavirus 2; virus entry, Animals; Antiviral Agents; COVID-19; Endocytosis; Influenza A virus; Mice; SARS-CoV-2; Virus Internalization |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit |
| Date Deposited: | 27 Jun 2023 05:51 |
| Last Modified: | 27 Jun 2023 06:58 |
| URI: | https://eprints.iisc.ac.in/id/eprint/82034 |
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