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Dengue Virus NS2B/NS3 Protease Inhibitors Exploiting the Prime Side
Kuan-Hung Lin1, Akbar Ali1, Linah Rusere1
1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Journal of Virology
|March 17, 2017
Summary
New cyclic peptides show promise as dengue virus (DENV) protease inhibitors. These novel compounds target both sides of the DENV protease active site, offering potential for more specific and less hydrophilic antiviral drugs.
Area of Science:
- Virology and Drug Discovery
- Structural Biology and Medicinal Chemistry
Background:
- Dengue virus (DENV) is a mosquito-borne flavivirus causing millions of infections globally, with no direct-acting antivirals currently available.
- The dengue virus NS2B/NS3 protease is essential for viral maturation and represents a key target for antiviral drug development.
- Existing DENV protease inhibitor designs primarily focus on the nonprime side of the active site, leading to limitations in specificity and hydrophilicity.
Purpose of the Study:
- To design and develop novel cyclic peptide inhibitors targeting the dengue virus NS2B/NS3 protease.
- To explore the potential of engaging both the prime and nonprime sides of the protease active site for enhanced inhibitor properties.
- To create potent and specific inhibitors with reduced hydrophilicity compared to current scaffolds.
Main Methods:
- Design of cyclic peptides based on aprotinin loops, incorporating interactions with both sides of the DENV protease active site.
- Optimization of peptide cyclization linker, length, and amino acid sequence.
- Biochemical assays to determine inhibitory activity against DENV3 wild-type protease, measuring binding affinity (K value).
Main Results:
- A series of cyclic peptides were designed and synthesized as inhibitors of dengue virus protease.
- The most potent cyclic peptide inhibitor achieved a K value of 2.9 μM against DENV3 wild-type protease.
- These findings demonstrate proof of concept for exploiting both sides of the DENV protease active site.
Conclusions:
- Cyclic peptides targeting both the prime and nonprime sides of the DENV protease active site are feasible inhibitor scaffolds.
- This approach offers a strategy to potentially improve specificity and reduce hydrophilicity in antiviral drug design for DENV.
- The developed cyclic peptides represent novel scaffolds for antiflaviviral inhibitor development, including for related viruses like Zika.
