This is an R01 application in response to RFA-AI-13-013 Partnerships for Biodefense (R01). Rickettsioses represent some of the most devastating human infections. These tick-borne diseases are caused by obligately intracellular bacteria of the genus Rickettsia, including typhus fever (Rickettsia prowazekii), an NIAID Category B Priority pathogen. It has been forecasted that temperature increases due to global climate change will lead to more widespread incidence of rickettsioses. In addition, a high infectivity and severe illness after inhalation make rickettsiae potential bioterrorism threats. Although rickettsil infections can be controlled by appropriate broad-spectrum antibiotic therapy if diagnosed early, up to 20% of misdiagnosed or untreated and 5% of treated Rocky Mountain spotted fever (RMSF) cases result in a fatal outcome. In fact, a fatality rate as high as 32% has been reported in hospitalized patients with Mediterranean spotted fever. Strains of R. prowazekii resistant to tetracycline and chloramphenicol have been developed in laboratories. Therefore, novel mechanism-based treatments are urgently needed. Our recent studies reveal that exchange protein directly activated by cAMP (Epac1) plays an important role in rickettsiosis. Deletion of Epac1 gene in mice protects them from fatal rickettsioses. Most importantly, we have developed first-in-class, small-molecule Epac specific-inhibitors (ESIs). Using these ESIs, we have further demonstrated that pharmacological inhibition of Epac in vivo recapitulates the Epac1-null phenotype: wild-type mice treated with an ESI are protected from fatal rickettsioses. These results indicate that Epac1 is a novel therapeutic target for potentially fatal rickettsiosis. In te present proposal, we will design, synthesize and optimize the lead candidates discovered in our laboratory for the discovery and development of more potent and specific ESIs with minimal toxicity, desired pharmacokinetic (PK) and pharmacodynamic (PD) properties. Optimized ESIs will be further analyzed for preclinical testing for efficacy and safety to identify drug candidate in animal models in vivo for the development of effective therapeutics for rickettsioses.

Public Health Relevance

Our study focuses on the preclinical development of novel drug candidates for the treatment of microbial infections caused by tick-borne bacteria Rickettsia, an NIAID Priority Pathogen and a potential agent for biological warfare.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI111464-04
Application #
9250048
Study Section
Special Emphasis Panel (ZAI1-AWA-M (J1))
Program Officer
Franceschi, Francois J
Project Start
2014-04-10
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
4
Fiscal Year
2017
Total Cost
$1,209,563
Indirect Cost
$83,092
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhu, Yingmin; Mei, Fang; Luo, Pei et al. (2017) A cell-based, quantitative and isoform-specific assay for exchange proteins directly activated by cAMP. Sci Rep 7:6200
Wang, Pingyuan; Liu, Zhiqing; Chen, Haiying et al. (2017) Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets. Bioorg Med Chem Lett 27:1633-1639
Liu, Zhiqing; Zhu, Yingmin; Chen, Haiying et al. (2017) Structure-activity relationships of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs). Bioorg Med Chem Lett 27:5163-5166
Almahariq, Muayad; Mei, Fang C; Cheng, Xiaodong (2016) The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention. Acta Biochim Biophys Sin (Shanghai) 48:75-81
Ye, Na; Chen, Haiying; Wold, Eric A et al. (2016) Therapeutic Potential of Spirooxindoles as Antiviral Agents. ACS Infect Dis 2:382-92
Banerjee, Upasana; Cheng, Xiaodong (2015) Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics. Gene 570:157-67
Ye, Na; Zhu, Yingmin; Chen, Haijun et al. (2015) Structure-Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists. J Med Chem 58:6033-47
Zhu, Yingmin; Chen, Haijun; Boulton, Stephen et al. (2015) Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 ""therapeutic window"". Sci Rep 5:9344