Nicotinamide-based Sirtuin 2 inhibitors as anti-HCMV agents.

Area of Science:

• Virology
• Molecular Biology
• Biochemistry

Background:

• Human cytomegalovirus (HCMV) is a major cause of illness and death in immunocompromised individuals and newborns.
• Viruses, including HCMV, rely on host cell proteins for replication and spread.
• Sirtuin 2 (SIRT2) is an NAD+-dependent deacetylase affecting protein function and stability, with potential roles in viral infections.

Purpose of the Study:

• To investigate the efficacy of novel small molecule inhibitors targeting SIRT2 against HCMV replication.
• To explore the impact of SIRT2 inhibition on HCMV infection dynamics.
• To examine the expression patterns of SIRT2 and SIRT1 during HCMV infection and in response to SIRT2 inhibitors.

Main Methods:

• Synthesis and testing of novel small molecule SIRT2 inhibitors.
• Assessment of antiviral activity against HCMV replication in vitro.
• Combination studies with standard antivirals (ganciclovir, letermovir).
• Indirect immunofluorescence to analyze SIRT2, SIRT1, and GAPDH expression in infected and treated cells.

Main Results:

• Two novel compounds demonstrated inhibition of SIRT2 activity and significant inhibition of HCMV replication.
• Combination therapy with existing antivirals showed an additive effect.
• SIRT2 and SIRT1 expression decreased over time in treated and untreated cells.
• HCMV infection led to increased SIRT2 and SIRT1 expression in infected cells, independent of treatment, unlike stable GAPDH expression.

Conclusions:

• Novel SIRT2 inhibitors show promise as a potential therapeutic strategy against HCMV.
• HCMV infection influences the expression of SIRT2 and SIRT1, suggesting a role for these sirtuins in the viral life cycle.
• Further research is necessary to elucidate the precise anti-HCMV mechanisms of SIRT2 inhibitors and the impact of HCMV on sirtuin expression.