Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models

Author:

Cao Xufeng1ORCID,Yang Dong2ORCID,Parvathareddy Jyothi2,Chu Yong-kyu3,Kim Eun Jung3,Fitz-Henley Jhewelle N.1ORCID,Li Xiaoyu1ORCID,Lukka Pradeep B.4ORCID,Parmar Keyur R.4ORCID,Temrikar Zaid H.4,Dhole Priya3,Adcock Robert Scott3ORCID,Gabbard Jon3,Bansal Shruti2,Lee Jasper5,Zalduondo Lillian2ORCID,Hayes Ernestine2ORCID,Stabenow Jennifer2ORCID,Meibohm Bernd4ORCID,Fitzpatrick Elizabeth A.25,Bailey Kevin6ORCID,Campos Rafael K.7ORCID,Julander Justin G.6ORCID,Rossi Shannan L.8ORCID,Chung Donghoon3ORCID,Jonsson Colleen B.245ORCID,Golden Jennifer E.19ORCID

Affiliation:

1. School of Pharmacy, Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI 53705, USA.

2. Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

3. Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.

4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

5. Departments of Microbiology, Immunology, Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

6. Institute for Antiviral Research, Utah State University, Logan, UT 84322, USA.

7. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.

8. Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.

9. Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.

Abstract

Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV, respectively) are mosquito-borne, neuroinvasive human pathogens for which no FDA-approved therapeutic exists. Besides the biothreat posed by these viruses when aerosolized, arthropod transmission presents serious health risks to humans, as demonstrated by the 2019 outbreak of EEE disease in the United States that resulted in 38 confirmed cases, 19 deaths, and neurological effects in survivors. Here, we describe the discovery of a 2-pyrrolidinoquinazolinone scaffold, efficiently synthesized in two to five steps, whose structural optimization resulted in profound antiviral activity. The lead quinazolinone, BDGR-49, potently reduced cellular VEEV and EEEV titers by >7 log at 1 μM and exhibited suitable intravenous and oral pharmacokinetic profiles in BALB/c mice to achieve excellent brain exposure. Outstanding in vivo efficacy was observed in several lethal, subcutaneous infection mouse models using an 8-day dosing regimen. Prophylactically administered BDGR-49 at 25 mg kg −1 per day fully protected against a 10× LD 50 VEEV Trinidad donkey (TrD) challenge in BALB/c mice. Similarly, we observed 70% protection when 10× LD 50 EEEV FL93-939–infected C57BL/6 mice were treated prophylactically with BDGR-49 at 50 mg kg −1 per day. Last, we observed 100% therapeutic efficacy when mice, challenged with 10× LD 50 VEEV TrD, were dosed at 48 hours after infection with BDGR-49 at 25 mg kg −1 per day. Mouse brain viral titers at 96 hours after infection were reduced to values near the limit of detection. Collectively, these results underscore the substantial development potential of a well-tolerated, brain-penetrant lead compound that shows promise in preventing and treating encephalitic alphavirus disease.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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