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Updated: Jun 18, 2025
Early Viral Entry Assays for the Identification and Evaluation of Antiviral Compounds
Published on: October 29, 2015
Novel sialidase inhibitors suppress mumps virus replication and infection
Tadanobu Takahashi1, Yuuki Kurebayashi1, Tadamune Otsubo2
1Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan.
Abstract:
The prevalent human pathogen, mumps virus (MuV; orthorubulavirus parotitidis) causes various complications and serious sequelae, such as meningitis, encephalitis, deafness, and impaired fertility. Direct-acting antivirals (DAAs) targeting MuV which can prevent mumps and mumps-associated complications and sequelae are yet to be developed. Paramyxoviridae family members, such as MuV, possess viral surface hemagglutinin-neuraminidase (HN) protein with sialidase activity which facilitates efficient viral replication. Therefore, to develop DAAs targeting MuV we synthesized MuV sialidase inhibitors. It is proposed that the viral HN has a single functional site for N-acetylneuraminic acid (Neu5Ac) binding and sialidase activity. Further, the known MuV sialidase inhibitor is an analog of Neu5Ac-2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA)-which lacks potency. DANA derivatives with higher MuV sialidase inhibitory potency are lacking. The MuV-HN-Neu5Ac binding site has a hydrophobic cavity adjacent to the C4 position of Neu5Ac. Exploiting this, here, we synthesized DANA derivatives with increasing hydrophobicity at its C4 position and created 3 novel sialidase inhibitors (Compounds 1, 2, and 3) with higher specificity for MuV-HN than DANA; they inhibited MuV replication step to greater extent than DANA. Furthermore, they also inhibited hemagglutination and the MuV infection step. The insight-that these 3 novel DANA derivatives possess linear hydrocarbon groups at the C4-hydroxyl group of DANA-could help develop highly potent sialidase inhibitors with high specificity for MuV sialidase, which may function as direct-acting MuV-specific antivirals.
Insights
Novel sialidase inhibitors were developed to combat mumps virus (MuV) by targeting its hemagglutinin-neuraminidase (HN) protein. These compounds show promise as direct-acting antivirals against MuV and its associated complications.
Area of Science:
- Virology
- Drug Discovery
- Biochemistry
Background:
- Mumps virus (MuV) causes significant health issues, including meningitis and encephalitis.
- Current treatments lack direct-acting antivirals (DAAs) specifically targeting MuV.
- The MuV hemagglutinin-neuraminidase (HN) protein is crucial for viral replication and a potential drug target.
Purpose of the Study:
- To synthesize and evaluate novel sialidase inhibitors targeting the MuV HN protein.
- To develop potent and specific DAAs for preventing mumps and its sequelae.
Main Methods:
- Synthesized DANA derivatives with increased hydrophobicity at the C4 position.
- Assessed MuV sialidase inhibitory activity and specificity compared to DANA.
- Evaluated inhibition of MuV replication, hemagglutination, and infection.
Main Results:
- Developed three novel DANA derivatives (Compounds 1, 2, and 3) with enhanced MuV-HN specificity.
- These compounds demonstrated greater inhibition of MuV replication, hemagglutination, and infection than DANA.
- The C4-modified DANA derivatives showed significant potential as MuV sialidase inhibitors.
Conclusions:
- Novel DANA derivatives with hydrophobic C4 modifications are potent MuV sialidase inhibitors.
- These compounds exhibit high specificity for MuV-HN, offering a promising strategy for developing MuV-specific DAAs.
- Further development could lead to effective treatments for mumps and its severe complications.
