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Home / Equine Research Bank / Sci Transl Med / Efficacy of a brain-penetrant antiviral in lethal Venezuelan...
Science translational medicine2023; 15(691); eabl9344; doi: 10.1126/scitranslmed.abl9344

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

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× LD50 VEEV Trinidad donkey (TrD) challenge in BALB/c mice. Similarly, we observed 70% protection when 10× LD50 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× LD50 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.
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Publication Date: 2023-04-12 PubMed ID: 37043558PubMed Central: PMC11577637DOI: 10.1126/scitranslmed.abl9344Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article presents the development and testing of a newly discovered compound, BDGR-49, capable of reducing the effects of neuroinvasive pathogens transmitted by mosquitoes, such as the Venezuelan and eastern equine encephalitis viruses. Structurally enhanced, this antiviral demonstrates its effectiveness in mice, reducing brain viral levels to near undetectable amounts and providing significant potential for future development.

Overview of the Research

  • The research focuses on the dangers posed by Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV respectively), mosquito-borne pathogens that can infect the brain, causing severe health risks to humans. These viruses pose significant health threats, especially to regions prone to mosquito-transmitted diseases, where seasonal outbreaks can have deadly consequences.
  • The researchers identified the lack of FDA-approved therapeutics for these viruses, thus prompting their work on developing an effective antiviral solution.

Antiviral Discovery and Efficacy

  • Scientists found a structurally distinct compound, a 2-pyrrolidinoquinazolinone scaffold, through several chemical optimization steps. This compound exhibits noteworthy antiviral properties. Their lead molecule, BDGR-49, effectively reduced cellular VEEV and EEEV titers significantly at a low concentration, and was able to penetrate the brain effectively.
  • The compound showcased impressive in-vivo efficacy in several severe infection mouse models, using an 8-day dosing regimen. Whether BDGR-49 was administered as prophylactic or therapeutic treatment, it demonstrated an excellent protective and therapeutic efficacy.

Prospective Future Development and Application

  • This promising new antiviral agent provides hope that its success in mouse models will translate into effective treatments for humans affected by these mosquito-borne diseases.
  • The study suggests that, with further optimization and testing, BDGR-49 could become a viable treatment for combating encephalitis due to alphaviruses.
  • Their extensive work highlights the potential of this brain-penetrant compound, not only in the prevention of such diseases, but also in the treatment of already infected patients, hence underscoring its potential for future development and possible FDA approval.

Cite This Article

APA
Cao X, Yang D, Parvathareddy J, Chu YK, Kim EJ, Fitz-Henley JN, Li X, Lukka PB, Parmar KR, Temrikar ZH, Dhole P, Adcock RS, Gabbard J, Bansal S, Lee J, Zalduondo L, Hayes E, Stabenow J, Meibohm B, Fitzpatrick EA, Bailey K, Campos RK, Julander JG, Rossi SL, Chung D, Jonsson CB, Golden JE. (2023). Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models. Sci Transl Med, 15(691), eabl9344. https://doi.org/10.1126/scitranslmed.abl9344

Publication

Science translational medicine
ISSN: 1946-6242
NlmUniqueID: 101505086
Country: United States
Language: English
Volume: 15
Issue: 691
Pages: eabl9344

Researcher Affiliations

Cao, Xufeng
  • School of Pharmacy, Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI 53705, USA.
Yang, Dong
  • Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Parvathareddy, Jyothi
  • Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Chu, Yong-Kyu
  • Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Kim, Eun Jung
  • Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Fitz-Henley, Jhewelle N
  • School of Pharmacy, Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI 53705, USA.
Li, Xiaoyu
  • School of Pharmacy, Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI 53705, USA.
Lukka, Pradeep B
  • Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Parmar, Keyur R
  • Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Temrikar, Zaid H
  • Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Dhole, Priya
  • Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Adcock, Robert Scott
  • Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Gabbard, Jon
  • Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Bansal, Shruti
  • Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Lee, Jasper
  • Departments of Microbiology, Immunology, Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Zalduondo, Lillian
  • Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Hayes, Ernestine
  • Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Stabenow, Jennifer
  • Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Meibohm, Bernd
  • Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Fitzpatrick, Elizabeth A
  • Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  • Departments of Microbiology, Immunology, Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Bailey, Kevin
  • Institute for Antiviral Research, Utah State University, Logan, UT 84322, USA.
Campos, Rafael K
  • Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Julander, Justin G
  • Institute for Antiviral Research, Utah State University, Logan, UT 84322, USA.
Rossi, Shannan L
  • Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Chung, Donghoon
  • Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Jonsson, Colleen B
  • Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  • Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  • Departments of Microbiology, Immunology, Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Golden, Jennifer E
  • School of Pharmacy, Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI 53705, USA.
  • Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.

MeSH Terms

  • Humans
  • Horses
  • Animals
  • Mice
  • United States
  • Encephalitis Virus, Venezuelan Equine
  • Encephalomyelitis, Eastern Equine
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • Mice, Inbred C57BL
  • Brain

Grant Funding

  • R01 AI118814 / NIAID NIH HHS
  • S10 OD016226 / NIH HHS
  • U19 AI142762 / NIAID NIH HHS

Conflict of Interest Statement

Competing interests: J.E.G., X.C., X.L., C.B.J., and D.C. are coinventors on a patent supported through the Wisconsin Alumni Research Foundation (WARF) on the quinazolinone series (U.S. Patent US2020049351).

References

This article includes 58 references
  1. Morens DM, Folkers GK, Fauci AS. Eastern equine encephalitis virus—Another emergent arbovirus in the United States.. New Engl. J. Med. 381, 1989–1992 (2019).
    pubmed: 31747726
  2. Lee VJ, Aguilera X, Heymann D, Wilder-Smith A. Preparedness for emerging epidemic threats: A Lancet Infectious Diseases Commission.. Lancet Infect. Dis. 20, 17–19 (2020).
    pmc: PMC7158988pubmed: 31876487
  3. Simpson S, Kaufmann MC, Glozman V, Chakrabarti A. Disease X: Accelerating the development of medical countermeasures for the next pandemic.. Lancet Infect. Dis. 20, e108–e115 (2020).
    pmc: PMC7158580pubmed: 32197097
  4. Petersen LR, Beard CB, Visser SN. Combatting the increasing threat of vector-borne disease in the United States with a national vector-borne disease prevention and control system.. Am. J. Trop. Med. Hyg. 100, 242–245 (2019).
    pmc: PMC6367643pubmed: 30499427
  5. . Global COVID-19 statistics. Coronovirus Resource Center (Johns Hopkins University, 2023) [accessed 10 March 2023].
  6. Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19.. Nat. Rev. Microbiol. 19, 141–154 (2021).
    pmc: PMC7537588pubmed: 33024307
  7. Lindsey NP, Martin SW, Staples JE, Fisher M. Notes from the field: Multistate outbreak of eastern equine encephalitis virus—United States, 2019.. Morb. Mortal. Wkly. Rep. 69, 50–51 (2020).
    pmc: PMC6973353pubmed: 31945032
  8. . Eastern equine encephalitis virus neuroinvasive disease cases reported by year, 2010–2019.. ArboNET, Arboviral Disease Branch, Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Vector-Borne Diseases; cdc.gov [accessed 13 August 2021].
  9. Millet N, Faiek S, Gurrieri D, Kals K, Adams W, Hamaty E, Trivedi M, Zeidwerg D. Deadly neuroinvasive mosquito-borne virus: A case of eastern equine encephalitis.. Perm. J. 25, 1–3 (2021).
    pmc: PMC8784058pubmed: 33970094
  10. Heberlein-Larson LA, Tan Y, Stark LM, Cannons AC, Shilts MH, Unnasch TR, Das SR. Complex epidemiological dynamics of eastern equine encephalitis virus in Florida.. Am. J. Trop. Med. Hyg. 100, 1266–1274 (2019).
    pmc: PMC6493969pubmed: 30860014
  11. Reichert E, Clase A, Bacetty A, Larsen J. Alphavirus antiviral drug development: Scientific gap analysis and prospective research areas.. Biosecur. Bioterror. 7, 413–427 (2009).
    pubmed: 20028250
  12. Holmes AC, Basore K, Fremont DH, Diamond MS. A molecular understanding of alphavirus entry.. PLOS Pathog. 16, e1008876 (2020).
    pmc: PMC7580943pubmed: 33091085
  13. Kim AS, Diamond MS. A molecular understanding of alphavirus entry and antibody protection.. Nat. Rev. Microbiol 1–12 (2022).
    pmc: PMC9734810pubmed: 36474012
  14. Calisher CH. Medically important arboviruses of the United States and Canada.. Clin. Microbiol. Rev. 7, 89–116 (1994).
    pmc: PMC358307pubmed: 8118792
  15. Silverman MA, Misasi J, Smole S, Feldman HA, Cohen AB, Santagata S, McManus M, Ahmed AA. Eastern equine encephalitis in children, Massachusetts and New Hampshire, USA, 1970–2010.. Emerg. Infect. Dis. 19, 194–201 (2013).
    pmc: PMC3559032pubmed: 23343480
  16. Ronca SE, Dineley KT, Paessler S. Neurological sequelae resulting from encephalitic alphavirus infection.. Front. Microbiol. 7, 959 (2016).
    pmc: PMC4913092pubmed: 27379085
  17. Aguilar PV, Estrada-Franco JG, Navarro-Lopez R, Ferro C, Haddow AD, Weaver SC. Endemic Venezuelan equine encephalitis in the Americas: Hidden under the dengue umbrella.. Future Virol. 6, 721–740 (2011).
    pmc: PMC3134406pubmed: 21765860
  18. Forrester NL, Wertheim JO, Dugan VG, Auguste AJ, Lin D, Adams AP, Chen R, Gorchakov R, Leal G, Estrada-Franco JG, Pandya J, Halpin RA, Hari K, Jain R, Stockwell TB, Das SR, Wentworth DE, Smith MD, Kosakovsky Pond SL, Weaver SC. Evolution and spread of Venezuelan equine encephalitis complex alphavirus in the Americas.. PLOS Negl. Trop. Dis. 11, e0005693 (2017).
    pmc: PMC5557581pubmed: 28771475
  19. Salimi H, Cain MD, Jiang X, Roth RA, Beatty WL, Sun C, Klimstra WB, Hou J, Klein RS. Encephalitic alphaviruses exploit caveola-mediated transcytosis at the blood-brain barrier for central nervous system entry.. MBio 11, e02731–19 (2020).
    pmc: PMC7018649pubmed: 32047126
  20. Phillips AT, Rico AB, Stauft CB, Hammond SL, Aboellail TA, Tjalkens RB, Olson KE. Entry sites of Venezuelan and western equine encephalitis viruses in the mouse central nervous system following peripheral infection.. J. Virol. 90, 5785–5796 (2016).
    pmc: PMC4886771pubmed: 27053560
  21. Sharma A, Knollmann-Ritschel B. Current understanding of the molecular basis of Venezuelan equine encephalitis virus pathogenesis and vaccine development.. Viruses 11, 164 (2019).
    pmc: PMC6410161pubmed: 30781656
  22. Honnold SP, Mossel EC, Bakken RR, Fisher D, Lind CM, Cohen JW, Eccleston LT, Spurgers KB, Erwin-Cohen R, Bradfute SB, Maheshwari RK, Glass PJ. Eastern equine encephalitis virus in mice I: Clinical course and outcome are dependent on route of exposure.. Virology J. 12, 152 (2015).
    pmc: PMC4588493pubmed: 26420265
  23. Kehn-Hall K, Bradfute SB. Understanding host responses to equine encephalitis virus infection: Implications for therapeutic development.. Expert Rev. Anti Infect. Ther. 20, 1551–1566 (2022).
    pubmed: 36305549
  24. Schroeder CE, Yao T, Sotsky J, Smith RA, Roy S, Chu Y-K, Guo H, Tower NA, Noah JW, McKellip S, Sosa M, Rasmussen L, Smith LH, White EL, Aubé J, Jonsson CB, Chung D, Golden JE. Development of (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336: Novel 2-amidinophenylbenzamides as potent inhibitors of Venezuelan equine encephalitis virus.. J. Med. Chem. 57, 8608–8621 (2014).
    pmc: PMC4207539pubmed: 25244572
  25. Ching K-C, Ng LFP, Chai CLL. A compendium of small molecule direct-acting and host-targeting inhibitors as therapies against alphaviruses.. J. Antimicrob. Chemother. 72, 2973–2989 (2017).
    pmc: PMC7110243pubmed: 28981632
  26. Jonsson CB, Cao X, Lee J, Gabbard JD, Chu Y-K, Fitzpatrick EA, Julander J, Chung D-H, Stabenow J, Golden JE. Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses.. Antiviral Res. 167, 25–34 (2019).
    pmc: PMC7305796pubmed: 30970271
  27. Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, Guthrie DB, Hager M, Kuiper DL, Lockwood MA, Mitchell DG, Natchus MG, Sticher ZM, Kolykhalov AA. The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection.. Antiviral Res. 171, 104597 (2019).
    pubmed: 31494195
  28. Ogorek TJ, Golden JE. Advances in the development of small molecule antivirals against equine encephalitic viruses.. Viruses 15, 413 (2023).
    pmc: PMC9958955pubmed: 36851628
  29. Kim AS, Austin SK, Gardner CL, Zuiani A, Reed DS, Trobaugh DW, Sun C, Basore K, Williamson LE, Crowe JE, Slifka MK, Fremont DH, Klimstra WB, Diamond MS. Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein.. Nat. Microbiol. 4, 187–197 (2019).
    pmc: PMC6294662pubmed: 30455470
  30. Williamson LE, Gilliland T Jr., Yadav PK, Binshtein E, Bombardi R, Kose N, Nargi RS, Sutton RE, Durie CL, Armstrong E, Carnahan RH, Walker LM, Kim AS, Fox JM, Diamond MS, Ohi MD, Klimstra WB, Crowe JE Jr.. Human antibodies protect against aerosolized eastern equine encephalitis virus infection.. Cell 183, 1884–1900.e23 (2020).
    pmc: PMC7806206pubmed: 33301709
  31. Burke CW, Froude JW, Rossi F, White CE, Moyer CL, Ennis J, Pitt ML, Streatfield S, Jones RM, Musiychuk K, Kervinen J, Zeitlin L, Yusibov V, Glass PJ. Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure.. PLOS Pathog. 15, e1008157 (2019).
    pmc: PMC6907853pubmed: 31790515
  32. Stromberg ZR, Fischer W, Bradfute SB, Kubicek-Sutherland JZ, Hraber P. Vaccine advances against Venezuelan, eastern, and western equine encephalitis viruses.. Vaccines (Basel) 8, 273 (2020).
    pmc: PMC7350001pubmed: 32503232
  33. Paessler S, Weaver SC. Vaccines for Venezuelan equine encephalitis.. Vaccine 27, D80–D85 (2009).
    pmc: PMC2764542pubmed: 19837294
  34. Reed DS, Glass PJ, Bakken RR, Barth JF, Lind CM, da Silva L, Hart MK, Rayner J, Alterson K, Custer M, Dudek J, Owens G, Kamrud KI, Parker MD, Smith J. Combined alphavirus replicon particle vaccine induces durable and cross-protective immune responses against equine encephalitis viruses.. J. Virol. 88, 12077–12086 (2014).
    pmc: PMC4178741pubmed: 25122801
  35. Trobaugh DW, Sun C, Dunn MD, Reed DS, Klimstra WB. Rational design of a live-attenuated eastern equine encephalitis virus vaccine through informed mutation of virulence determinants.. PLOS Pathog. 15, e1007584 (2019).
    pmc: PMC6386422pubmed: 30742691
  36. Powers AM. Resurgence of interest in eastern equine encephalitis virus vaccine development.. J. Med. Entom. 59, 20–26 (2021).
    pubmed: 34734632
  37. Guerrero-Arguero I, Tellez-Freitas CM, Weber KS, Berges BK, Robison RA, Pickett BE. Alphaviruses: Host pathogenesis, immune response, and vaccine & treatment updates.. J. Gen. Virol. 102, (2021).
    pubmed: 34435944
  38. Hayes EB, Staples JE, in Principles and Practice of Pediatric Infectious Diseases, Long SS, Ed. (Elsevier, ed. 4, 2012), pp. 1097–1099.e1092.
  39. Schroeder CE, Neuenswander SA, Yao T, Aubé J, Golden JE. One-pot, regiospecific assembly of (E)-benzamidines from δ- and γ-amino acids via an intramolecular amino-quinazolinone rearrangement.. Org. Biomol. Chem. 14, 3950–3955 (2016).
    pmc: PMC4838566pubmed: 27050086
  40. Jaffett VA, Nerurkar A, Cao X, Guzei IA, Golden JE. Telescoped synthesis of C3-functionalized (E)-arylamidines using Ugi–Mumm and regiospecific quinazolinone rearrangements.. Org. Biomol. Chem. 17, 3118–3128 (2019).
    pmc: PMC6426674pubmed: 30730519
  41. Demeunynck M, Baussanne I. Survey of recent literature related to the biologically active 4(3H)-quinazolinones containing fused heterocycles.. Curr. Med. Chem. 20, 794–814 (2013).
    pubmed: 23276134
  42. Resende DISP, Boonpothong P, Sousa E, Kijjoa A, Pinto MMM. Chemistry of the fumiquinazolines and structurally related alkaloids.. Nat. Prod. Rep. 36, 7–34 (2019).
    pubmed: 30091435
  43. Rusnak JM, Glass PJ, Weaver SC, Sabourin CL, Glenn AM, Klimstra W, Badorrek CS, Nasar F, Ward LA. Approach to strain selection and the propagation of viral stocks for Venezuelan equine encephalitis virus vaccine efficacy testing under the animal rule.. Viruses 11, 807 (2019).
    pmc: PMC6784384pubmed: 31480472
  44. Ma H, Lundy JD, Cottle EL, O’Malley KJ, Trichel AM, Klimstra WB, Hartman AL, Reed DS, Teichert T. Applications of minimally invasive multimodal telemetry for continuous monitoring of brain function and intracranial pressure in macaques with acute viral encephalitis.. PLOS ONE 15, e0232381 (2020).
    pmc: PMC7316240pubmed: 32584818
  45. Albe JR, Ma H, Gilliland TH, McMillen CM, Gardner CL, Boyles DA, Cottle EL, Dunn MD, Lundy JD, O’Malley KJ, Salama N, Walters AW, Pandrea I, Teichert T, Klimstra WB, Reed DS, Hartman AL. Physiological and immunological changes in the brain associated with lethal eastern equine encephalitis virus in macaques.. PLOS Pathog. 17, e1009308 (2021).
    pmc: PMC7886169pubmed: 33534855
  46. Skidmore AM, Adcock RS, Jonsson CB, Golden JE, Chung DH. Benzamidine ML336 inhibits plus and minus strand RNA synthesis of Venezuelan equine encephalitis virus without affecting host RNA production.. Antiviral Res. 174, 104674 (2020).
    pmc: PMC6935354pubmed: 31816348
  47. Chung DH, Jonsson CB, Tower NA, Chu YK, Sahin E, Golden JE, Noah JW, Schroeder CE, Sotsky JB, Sosa MI, Cramer DE, McKellip SN, Rasmussen L, White EL, Schmaljohn CS, Julander JG, Smith JM, Filone CM, Connor JH, Sakurai Y, Davey RA. Discovery of a novel compound with anti-venezuelan equine encephalitis virus activity that targets the nonstructural protein 2.. PLOS Pathog. 10, e1004213 (2014).
    pmc: PMC4072787pubmed: 24967809
  48. Lee J, Parvathareddy J, Yang D, Bansal S, O’Connell K, Golden JE, Jonsson CB. Emergence and magnitude of ML336 resistance in venezuelan equine encephalitis virus depend on the microenvironment.. J. Virol. 94, e00317–20 (2020).
    pmc: PMC7592223pubmed: 32878897
  49. Ning X, Guo Y, Wang X, Ma X, Tian C, Shi X, Zhu R, Cheng C, Du Y, Ma Z, Zhang Z, Liu J. Design, synthesis, and biological evaluation of (E)-3,4-dihydroxystyryl aralkyl sulfones and sulfoxides as novel multifunctional neuroprotective agents.. J. Med. Chem. 57, 4302–4312 (2014).
    pubmed: 24697335
  50. Di L, Kerns EH, Bezar IF, Petusky SL, Huang Y. Comparison of blood-brain barrier permeability assays: In situ brain perfusion, MDR1-MDCKII and PAMPA-BBB.. J. Pharm. Sci. 98, 1980–1991 (2009).
    pubmed: 18837012
  51. Wang Q, Rager JD, Weinstein K, Kardos PS, Dobson GL, Li J, Hidalgo IJ. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier.. Int. J. Pharm. 288, 349–359 (2005).
    pubmed: 15620875
  52. Julander JG, Skirpstunas R, Siddharthan V, Shafer K, Hoopes JD, Smee DF, Morrey JD. C3H/HeN mouse model for the evaluation of antiviral agents for the treatment of Venezuelan equine encephalitis virus infection.. Antiviral Res. 78, 230–241 (2008).
    pmc: PMC2396595pubmed: 18313150
  53. Yan G, Zekarias BL, Li X, Jaffett VA, Guzei IA, Golden JE. Divergent 2-Chloroquinazolin-4(3H)-one rearrangement: Twisted-cyclic guanidine formation or ring-fused N-acylguanidines via a domino process.. Chem. Euro. J. 26, 2486–2492 (2020).
    pmc: PMC7071832pubmed: 31912567
  54. Ryan MC, Kim E, Cao X, Reichard W, Ogorek TJ, Das P, Jonsson CB, Baudry J, Chung D-H, Golden JE. Piperazinobenzodiazepinones: New encephalitic alphavirus inhibitors via ring expansion of 2-dichloromethylquinazolinones.. ACS Med. Chem. Lett. 13, 546–553 (2022).
    pmc: PMC9014857pubmed: 35450382
  55. Li X, Golden JE. Construction of N-Boc-2-alkylaminoquinazolin-4(3h)-ones via a three-component, one-pot protocol mediated by copper(II) chloride that spares enantiomeric purity.. Adv. Synth. Catal. 363, 1638–1645 (2021).
    pmc: PMC8048503pubmed: 33867902
  56. Chung DH, Golden JE, Adcock RS, Schroeder CE, Chu YK, Sotsky JB, Cramer DE, Chilton PM, Song C, Anantpadma M, Davey RA, Prodhan AI, Yin X, Zhang X. Discovery of a broad-spectrum antiviral compound that inhibits pyrimidine biosynthesis and establishes a type 1 interferon-independent antiviral state.. Antimicrob. Agents Chemother. 60, 4552–4562 (2016).
    pmc: PMC4958224pubmed: 27185801
  57. Adcock RS, Chu YK, Golden JE, Chung DH. Evaluation of anti-Zika virus activities of broad-spectrum antivirals and NIH clinical collection compounds using a cell-based, high-throughput screen assay.. Antiviral Res. 138, 47–56 (2017).
    pubmed: 27919709
  58. Raab GM. Comparison of a logistic and a mass-action curve for radioimmunoassay data.. Clin. Chem. 29, 1757–1761 (1983).
    pubmed: 6616820
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