1. Intracellular delivery of nuclear localization sequence peptide mitigates COVID-19 by inhibiting nuclear transport of inflammation-associated transcription factors.
- Author
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Lee S, Yoon SS, Jo M, Kang M, Lee S, Seo YJ, Park S, Paik YK, and Jo D
- Subjects
- Mice, Animals, Humans, Transcription Factors metabolism, Active Transport, Cell Nucleus, SARS-CoV-2, NF-kappa B metabolism, Inflammation, Cytokines metabolism, Peptides metabolism, COVID-19
- Abstract
The novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), can trigger dysregulated immune responses known as the cytokine release syndrome (CRS), leading to severe organ dysfunction and respiratory distress. Our study focuses on developing an improved cell-permeable nuclear import inhibitor (iCP-NI), capable of blocking the nuclear transport of inflammation-associated transcription factors, specifically nuclear factor kappa B (NF-κB). By fusing advanced macromolecule transduction domains and nuclear localization sequences from human NF-κB, iCP-NI selectively interacts with importin α5, effectively reducing the expression of proinflammatory cytokines. In mouse models mimic SARS-CoV-2-induced pneumonitis, iCP-NI treatment demonstrated a significant decrease in mortality rates by suppressing proinflammatory cytokine production and immune cell infiltration in the lungs. Similarly, in hamsters infected with SARS-CoV-2, iCP-NI effectively protected the lung from inflammatory damage by reducing tumor necrosis factor-α, interleukin-6 (IL-6), and IL-17 levels. These promising results highlight the potential of iCP-NI as a therapeutic approach for COVID-19-related lung complications and other inflammatory lung diseases., Competing Interests: Declaration of interests D.J. is the founding scientist of Cellivery Therapeutics, Inc.; Y.-K.P. is a member of the board of directors of Cellivery Therapeutics, Inc., and distinguished research professor emeritus of Yonsei University, Korea. M.J. is a student at the medical college of the University of Tennessee. All of the other authors are employees of Cellivery Therapeutics, Inc. Thus, those authors disclose a financial interest and hold employee stock options in the company. Cellivery Therapeutics, Inc. has filed patents for “advanced macromolecule transduction domain (aMTD) sequences for improvement of cell permeability, polynucleotides encoding the same, method to identify the unique features of aMTDs comprising the same, method to develop the aMTD sequences comprising the same.” The relevant application numbers are PCT/KR2015/008544 and PCT/KR2016/009405 (registered). aMTD patents are currently registered in the United States (15/503117), Republic of Korea (10-2017-7005079), Japan (2017–510405), Australia (2015304194), Canada (2957501), European Patent Office (15833496.1), and China (201580044116.8). In addition, the use of candidate (iCP-NI) has filed patents for “cytokine storm suppressing anti-sepsis agent.” The relevant number is PCT/KR2021/001976 (applied). iCP-NI patents are currently reviewed in the United States (17/783,822), India (202227039966), European Patent Office (21757172.8), Brazil (1120220117442), China (202180007013.X), Canada (3160603), and Japan (2022–540791). Provisional patent of iCP-NI for COVID-19 has applied for the Republic of Korea (10-2022-0088647) and the United States (63/392,272). There are no further patents, products in development, or marketed products to declare. The Phase I clinical trial of iCP-NI is ongoing in the United States as “iCP-NI - Safety, Tolerability, Pharmacokinetic, and Immunogenicity Study in Healthy Male and Female Subjects” (https://clinicaltrials.gov identifier: NCT05740280, approved by US FDA: IND158118)., (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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