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Substrate-based peptidomimetic inhibitors of the Murray Valley encephalitis virus NS2B/NS3 serine protease: a P1-P4
Melgious Jin Yan Ang1, Gerald Han Jie Yong, Anders Poulsen
1Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, Singapore 138669, Singapore.
Abstract:
Murray Valley encephalitis is an infectious disease spread by a mosquito-borne virus endemic in Papua New Guinea and northern Australia. In the past decade, it has spread to various regions of Australia and there is currently no therapeutic treatment against this disease. An attractive drug target is the viral serine protease NS2B/NS3, a critical enzyme involved in viral replication. Herein, we report the inhibitory activities of 37 C-terminal agmatine peptidomimetic inhibitors which led to the design of a novel structurally-constrained competitive inhibitor 38 possessing a Ki of 2.5±0.5 μM. We believe our data provides crucial insights into the viral protease active site specificity which could be used to facilitate drug design against Murray Valley encephalitis viral infections.
Insights
Researchers developed a novel competitive inhibitor for Murray Valley encephalitis virus. This discovery offers a potential new therapeutic strategy against this mosquito-borne infectious disease.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- Murray Valley encephalitis (MVE) is a mosquito-borne viral disease endemic to Papua New Guinea and northern Australia.
- MVE has expanded its reach across Australia in the last decade, posing a growing public health concern.
- Currently, no effective therapeutic treatments exist for MVE infections.
Purpose of the Study:
- To identify and design novel inhibitors targeting the MVE viral serine protease NS2B/NS3.
- To explore the structure-activity relationships of C-terminal agmatine peptidomimetics as potential antiviral agents.
- To provide insights into the MVE protease active site for future drug development.
Main Methods:
- Synthesis and evaluation of 37 C-terminal agmatine peptidomimetic inhibitors.
- Design and characterization of a novel structurally-constrained competitive inhibitor (compound 38).
- Determination of the inhibition constant (Ki) for the lead compound.
Main Results:
- 37 peptidomimetic inhibitors were synthesized and tested for their inhibitory activities.
- A novel competitive inhibitor, compound 38, was designed and synthesized.
- Compound 38 exhibited a Ki of 2.5±0.5 μM against the MVE viral protease.
Conclusions:
- The study identified potent inhibitors of the MVE viral serine protease NS2B/NS3.
- A novel competitive inhibitor demonstrates significant potential for MVE therapeutic development.
- The findings offer crucial insights into viral protease active site specificity, aiding future drug design efforts against MVE.
