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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global public health crisis due to extensive viral transmission. In situ RNA mapping has revealed angiotensin-converting enzyme 2 (ACE2) expression to be highest in the nose and lower in the lung, pointing to nasal susceptibility as a predominant route for infection and the cause of subsequent pulmonary effects. By blocking viral attachment and entry at the nasal airway using a cyclodextrin-based formulation, a preventative therapy can be developed to reduce viral infection at the site of entry. Here, we assess the safety and antiviral efficacy of cyclodextrin-based formulations. From these studies, hydroxypropyl beta-cyclodextrin (HPBCD) and hydroxypropyl gamma-cyclodextrin (HPGCD) were then further evaluated for antiviral effects using SARS-CoV-2 pseudotypes. Efficacy findings were confirmed with SARS-CoV-2 Delta variant infection of Calu-3 cells and using a K18-hACE2 murine model. Intranasal pre-treatment with HPBCD-based formulations reduced viral load and inflammatory signaling in the lung. In vitro efficacy studies were further conducted using lentiviruses, murine hepatitis virus (MHV), and influenza A virus subtype H1N1. These findings suggest HPBCD may be used as an agnostic barrier against transmissible pathogens, including but not limited to SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/ijms25042061","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T03:36:17Z","timestamp":1707363377000},"page":"2061","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Hydroxypropyl-Beta Cyclodextrin Barrier Prevents Respiratory Viral Infections: A Preclinical Study"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2932-0844","authenticated-orcid":false,"given":"Angela","family":"Lu","sequence":"first","affiliation":[{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8939-6069","authenticated-orcid":false,"given":"Brandon","family":"Ebright","sequence":"additional","affiliation":[{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aditya","family":"Naik","sequence":"additional","affiliation":[{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui L.","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noam A.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3069-0826","authenticated-orcid":false,"given":"Jean-Marie C.","family":"Bouteiller","sequence":"additional","affiliation":[{"name":"Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90007, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianluca","family":"Lazzi","sequence":"additional","affiliation":[{"name":"Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90007, USA"},{"name":"Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5941-6690","authenticated-orcid":false,"given":"Stan G.","family":"Louie","sequence":"additional","affiliation":[{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark S.","family":"Humayun","sequence":"additional","affiliation":[{"name":"Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90007, USA"},{"name":"Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9628-3425","authenticated-orcid":false,"given":"Isaac","family":"Asante","sequence":"additional","affiliation":[{"name":"Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA"},{"name":"Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5086","DOI":"10.1016\/j.vaccine.2007.03.046","article-title":"The Annual Impact of Seasonal Influenza in the US: Measuring Disease Burden and Costs","volume":"25","author":"Molinari","year":"2007","journal-title":"Vaccine"},{"key":"ref_2","unstructured":"DeMartino, J.M.N., Foroughi, C., Gaburo, K., Radtke, T., Kirson, N., and Krishnarajah, G. (2022, January 11\u201314). Annual Economic burden of respiratory syncytial virus infections among the 60+ population in the United States. 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