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Updated: Jun 6, 2026
04:23
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
Small molecule inhibitors that selectively block dengue virus methyltransferase
Siew Pheng Lim1, Louis Sebastian Sonntag, Christian Noble
1Novartis Institute for Tropical Diseases, 05-01 Chromos, Singapore. siew_pheng.lim@novartis.com
The Journal of Biological Chemistry
|December 15, 2010
Summary
Researchers developed novel dengue virus methyltransferase inhibitors by targeting a conserved flavivirus cavity. This strategy enhances selectivity, overcoming a key challenge in developing methyltransferase-based therapeutics.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Flavivirus methyltransferases (MTases) are crucial for viral replication.
- A conserved cavity adjacent to the S-adenosyl-methionine (SAM) binding site was identified in Flavivirus MTases.
- Developing selective MTase inhibitors is challenging due to similarities with human enzymes.
Purpose of the Study:
- To design and synthesize novel inhibitors targeting the identified flavivirus-conserved cavity.
- To evaluate the inhibitory activity and selectivity of these compounds against dengue virus MTase.
- To elucidate the structural basis for inhibitor binding and selectivity.
Main Methods:
- Crystal structure analysis of Flavivirus MTases.
- Chemical derivatization of S-adenosyl-homocysteine (SAH) to create novel inhibitors.
- Enzyme inhibition assays to determine activity and selectivity.
- Co-crystallization of dengue virus MTase with SAH derivatives.
Main Results:
- Novel SAH derivatives were synthesized, with substituents designed to occupy the conserved flavivirus cavity.
- These derivatives exhibited improved and selective inhibitory activity against dengue virus MTase.
- Structural analysis revealed that the N6-substituent bound within the cavity, inducing conformational changes.
- Inhibitors showed no significant activity against related human enzymes.
Conclusions:
- Targeting the conserved flavivirus cavity is a viable strategy for developing selective MTase inhibitors.
- This approach overcomes a significant hurdle in the development of MTase-based therapeutics.
- The findings pave the way for more effective antiviral therapies targeting flaviviruses.
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