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Human infections are typically from mosquito bites,\n                        although cases from respiratory exposure in laboratory accidents have been\n                        documented. In addition to natural mosquito-borne infection, the potential\n                        biothreat inherent in the ability to disseminate these viruses via the\n                        respiratory route has driven the development of antiviral drugs for this\n                        route of exposure. To address this gap, we tested the prophylactic\n                        administration of a novel brain-penetrant, antiviral, BDGR-49, against a\n                        lethal intranasal challenge of VEEV, WEEV, or EEEV in BALB\/c mouse model.\n                        BDGR-49 conferred 100% protection with 6 mg kg\n              <jats:sup>\u22121<\/jats:sup>\n              twice per\n                        day for 6 days for VEEV, but not EEEV or WEEV. By 8 days post-infection\n                        (dpi), infectious virus, viral RNA, and viral antigen in the brain of\n                        BDGR-49-treated mice were significantly reduced. Brains of VEEV\n                        TrD-infected, BDGR-49-treated mice showed a significant reduction in the\n                        expression of genes associated with inflammation (\n              <jats:italic toggle=\"yes\">IFNB1<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">TNF<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">IL6<\/jats:italic>\n              , and\n              <jats:italic toggle=\"yes\">CCL5<\/jats:italic>\n              )\n                        and cell death (\n              <jats:italic toggle=\"yes\">CASP4<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">GSDMD<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">PYCARD<\/jats:italic>\n              , and\n              <jats:italic toggle=\"yes\">ZBP1<\/jats:italic>\n              ). At dpi 14,\n                        histopathology showed that neuronal lesions and inflammatory cell\n                        infiltrates were essentially absent, and viral antigen was not detected in\n                        the brains of VEEV TrD-infected, BDGR-49-treated mice. In summary, although\n                        BDGR-49 treatment showed significant promise for the treatment of mice\n                        exposed intranasally to VEEV, the more rapid and efficient entry of EEEV and\n                        WEEV by this route into the central nervous system will require additional\n                        optimization of the dosing regimen.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>Prophylactic and therapeutic treatment of viruses that cause encephalitis\n                            requires fast-acting drugs that rapidly penetrate the blood-brain\n                            barrier. Currently, clinicians have only a limited set of antivirals for\n                            the treatment of neurotropic infections such as herpesviruses or HIV-1,\n                            and none for alphaviruses, and treatment outcomes remain poor. New\n                            medical countermeasures will address the gap in treatment of viral\n                            encephalitis such as those caused by the neurotropic alphaviruses and\n                            others.<\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01679-24","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T14:57:32Z","timestamp":1755010652000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["The antiviral BDGR-49 provides protection from lethal, neurotropic                    Venezuelan equine encephalitis virus intranasal infection in                    mice"],"prefix":"10.1128","volume":"99","author":[{"given":"Evan P.","family":"Williams","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology and Biochemistry, College of Medicine, The University of Tennessee Health Science 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Immunology and Biochemistry, College of Medicine, The University of Tennessee Health Science Center","place":["Memphis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler J.","family":"Ogorek","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Wisconsin-Madison","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Saini","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers The State University of New Jersey","place":["Piscataway, USA"]},{"name":"Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey","place":["Piscataway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Iulek","sequence":"additional","affiliation":[{"name":"Department of Chemistry, State University of Ponta Grossa","place":["Ponta Grossa, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc Xavier","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers The State University of New Jersey","place":["Piscataway, USA"]},{"name":"Department of Chemistry and Chemical Biology, Rutgers The State University of New Jersey","place":["Piscataway, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy","family":"Arnold","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers The State University of New Jersey","place":["Piscataway, USA"]},{"name":"Department of Chemistry and Chemical Biology, Rutgers The State University of New 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