Anti-Flavivirus Therapeutic Compounds

Researchers at Wadsworth Center have identified several small molecule compounds that inhibit flaviviral methyltransferase (Mtase) replication with two of these compounds, NSC 12155 and NSC 306711, showing broad spectrum activity and low cytotoxicity.  Recently and particularly, flavivirus NS5 Mtase has become an attractive target for therapeutic inventions because it is responsible for directing flaviviral RNA cap formation that is critical for viral replication.

Although vaccines for humans are currently available for Yellow Fever virus (YFV), Japanese encephalitis virus (JEV), and Tick-borne Encephalitis virus (TBEV), no clinically approved vaccine or antiviral therapy for humans is available for West Nile virus (WNV) and Dengue virus (DENV).  Therefore, it is a priority to develop and improve vaccines and antiviral agents for prevention and treatment of flavivirus infections.

Results

Virtual screening was performed on the Diversity Set II library of 1,364 compounds from the National Cancer Institute Developmental Therapeutics Program (NCI DTP).  Functional analysis indicated that four compounds, NSC 12155 and NSC 125910, NSC 306711 and NSC 610930, inhibited both the N7 and 2’-O Mtase functions.  Cytotoxicity and antiviral analyses indicated that they also inhibited the virus growth with low micromolar IC50 in cell culture.  Particularly, compounds NSC 12155 and 306711 displayed higher therapeutic indexes and broad antiviral spectrum.  Comparing these to known inhibitors revealed shared predicted contacts which could be further optimized with simple substitutions.

fliviviral-1

flaviviral-2 

Applications

  • Broad spectrum treatment potential for small molecular drugs inhibiting flavivirus infections
  • Optimizing candidate compounds by focusing on enhanced binding affinities leading to more potent and specific inhibitors for increased efficacy in treating flavivirus infections

Advantages

  • Compounds offering new therapeutic leads in flavivirus infections that lack any approved therapies.
  • Several inhibitory compounds that project into the SAM-binding cleft with additional residues outside the SAM-binding site confer specificity.
  • Two compounds that bind in one of the two identified Mtase RNA binding sites.
  • Identified nucleoside analogs that appear to bind to both GTP & SAM-binding pockets, inhibiting Mtase activity in vitro and viral replication.

State of Development

Health Research, Inc. is seeking companies interested in commercializing candidate compounds for treating patients with flavivirus infections.

Patents

Patent Pending

Licensing Potential

Available for License.

Inventors

Hongmin Li, Ph.D.
Laura D. Kramer, Ph.D.
Nilesh K. Banavali, Ph.D.

Publications

M Brecher, H Chen, B Liu, NK Banavali, SA Jones, J Zhang, Z Li, LD Kramer, H Li. Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase. Plos One, 2015 June 22, 10(6): e0130062. DOI:  10.1371/journal.pone.0130062. eCollection 2015.

H Chen, M Brecher, NK Banavali, SA Jones, J Zhang, Z Li, LD Kramer, H Li.  Identification and Characterization of Novel Broad Spectrum Inhibitors of the Flavivirus Methyltransferase. American Chemical Society. Infectious Diseases, 2015, 1(8), pp 340-349 DOI:  10.1021/acsinfecdis.5b00070.   Publication date July 31, 2015.

Contact

Diane L. Borghoff, B.S., M.S.
Marketing & Licensing Associate – Intellectual Property
Health Research, Inc. – 150 Broadway – Suite 560, Menands, New York 12204-2719 U.S.A.
Phone 518-431-1213 Fax 518-431-1234
E-mail: Diane.Borghoff@healthresearch.org Website: www@healthresearch.org