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Published on: October 28, 2019
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Human Cytomegalovirus Replication Is Inhibited by the Autophagy-Inducing Compounds Trehalose and SMER28 through
Alex E Clark1,2, Maite Sabalza1,2, Philip L S M Gordts3,4
1Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, California, USA.
Journal of Virology
|December 15, 2017
Summary
New autophagy-inducing compounds, trehalose and SMER28, show promise in inhibiting human cytomegalovirus (HCMV) replication. These drugs offer a less toxic alternative for treating HCMV infections, a leading cause of birth defects.
Area of Science:
- Virology
- Cell Biology
- Drug Discovery
Background:
- Human cytomegalovirus (HCMV) is a significant cause of congenital disabilities, with existing treatments exhibiting high toxicity.
- Autophagy modulation presents a novel strategy for antiviral therapy, leveraging the virus's dependence on autophagy inhibition.
Purpose of the Study:
- To elucidate the mechanism by which trehalose inhibits HCMV replication.
- To introduce SMER28 as an additional autophagy inducer with potential HCMV inhibitory effects.
- To compare the mechanisms of action and cellular effects of trehalose and SMER28 on HCMV.
Main Methods:
- Investigated trehalose-induced cellular changes, including vacuolation, acidification, and protein levels (Rab7, Rab11).
- Assessed SMER28's impact on HCMV early protein production and viral genome replication.
- Evaluated the effects of both compounds on autophagy and cellular glucose uptake.
Main Results:
- Trehalose induced vacuolation, acidification, and altered Rab protein levels, suggesting virion degradation via autophagy.
- SMER28 inhibited HCMV early protein synthesis and viral replication in a cell-type-dependent manner, with distinct cellular effects from trehalose.
- Both compounds demonstrated efficacy against HCMV, with trehalose promoting degradation and SMER28 reducing viral protein production.
Conclusions:
- Trehalose may inhibit HCMV by redirecting virions to acidified compartments for degradation, modulated by Rab7 and Rab11.
- SMER28 offers an alternative HCMV inhibition mechanism by reducing viral protein expression.
- These findings support autophagy modulation as a viable strategy for developing less toxic HCMV therapeutics.
