The significant burden that results from dengue virus infection combined with the absence of effective vaccines or drugs makes the development of novel therapeutics a high priority. The goal of our research is to identify and optimize compounds that target essential host factors to further our understanding of host-virus interactions and to validate host targets and lead compounds for further development as potential new classes of anti-viral agents. Our strategy is to target essential host factors by developing selective, covalent cysteine-directed inhibitors. The success of covalent inhibitors has been amply demonstrated by the thirtynine FDA-approved drugs that are highly effective in humans. We recently discovered a substituted quinolone, QL-XII-47, that is a potent inhibitor of the four dengue serotypes (EC90 400nM) at concentrations that are non-cytotoxic. Preliminary data indicate that QL-XII-47 acts via a host factor to inhibit DENV at a point late in viral entry. QL-XII- 47 has exhibited inhibitory activity against a number of other viruses within and beyond the Flavivirus family. We will utilize a combination of medicinal chemistry, chemical biology, chemical proteomics, and virology (1) to understand the structural features required to achieve antiviral activity and to obtain analogs with suitable pharmacological properties to enable in vivo experiments; (2) to examine the target and mechanism of action responsible for the potent antiviral activity of QL-XII-47 and related compounds in vitro; and (3) to examine the spectrum of QL-XII-47 s antiviral activities against additional Biodefense Viruses. The goal of this proposal is to identify covalent inhibitors of essential host-factor targets that exhibit broad antiviral activity in vitro and that are efficacious in a murine model of dengue virus infection. Further development of this agent and elucidation of its molecular target(s) may provide the first host-directed pharmacological approach for treating dengue virus infection. The strategy of developing cysteine-directed covalent inhibitors of host factors may provide a new and general paradigm for developing host-directed agents with the potential to broadly protect against many infectious agents.

Public Health Relevance

Dengue virus is the most widespread mosquito-borne virus in the world today and the cause of significant human disease;however, there currently are no vaccines or specific antiviral therapies to prevent or to treat dengue virus infection. The proposed experiments will develop small molecules that inhibit dengue virus by covalently modifying host factors required for viral replication.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DDS-M (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
United States
Zip Code
de Wispelaere, Melissanne; Lian, Wenlong; Potisopon, Supanee et al. (2018) Inhibition of Flaviviruses by Targeting a Conserved Pocket on the Viral Envelope Protein. Cell Chem Biol 25:1006-1016.e8
Huang, Nai-Jia; Pishesha, Novalia; Mukherjee, Jean et al. (2017) Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin. Nat Commun 8:423
Mertins, Philipp; Przybylski, Dariusz; Yosef, Nir et al. (2017) An Integrative Framework Reveals Signaling-to-Transcription Events in Toll-like Receptor Signaling. Cell Rep 19:2853-2866
Nair, Dhanalakshmi R; Chen, Ji; Monteiro, João M et al. (2017) A quinolinol-based small molecule with anti-MRSA activity that targets bacterial membrane and promotes fermentative metabolism. J Antibiot (Tokyo) 70:1009-1019
Choo, Min-Kyung; Sano, Yasuyo; Kim, Changhoon et al. (2017) TLR sensing of bacterial spore-associated RNA triggers host immune responses with detrimental effects. J Exp Med 214:1297-1311
de Wispelaere, Mélissanne; Carocci, Margot; Liang, Yanke et al. (2017) Discovery of host-targeted covalent inhibitors of dengue virus. Antiviral Res 139:171-179
Umetsu, Dale T (2017) Mechanisms by which obesity impacts upon asthma. Thorax 72:174-177
Zheng, Huiqing; Colvin, Christopher J; Johnson, Benjamin K et al. (2017) Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence. Nat Chem Biol 13:218-225
Coulson, Garry B; Johnson, Benjamin K; Zheng, Huiqing et al. (2017) Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics. Cell Chem Biol 24:993-1004.e4
Carocci, Margot; Yang, Priscilla L (2016) Lactimidomycin is a broad-spectrum inhibitor of dengue and other RNA viruses. Antiviral Res 128:57-62

Showing the most recent 10 out of 417 publications