The Telomerase Inhibitor MST-312 Interferes with Multiple Steps in the Herpes Simplex Virus Life Cycle

Abstract

The life cycle of herpes simplex virus (HSV) has the potential to be further manipulated to yield novel, more effective therapeutic treatments. Recent research has demonstrated that HSV-1 can increase telomerase activity and that expression of the catalytic component of telomerase, telomerase reverse transcriptase (TERT), alters sensitivity to HSV-dependent apoptosis. Telomerase is a cellular enzyme that synthesizes nucleotide repeats at the ends of chromosomes (telomeres), which prevents shortening of the 3= ends of DNA with each cell division. Once telomeres reach a critical length, cells undergo senescence and apoptosis. Here, we used a cell-permeable, reversible inhibitor of the telomerase enzyme, MST-312, to investigate telomerase activity during HSV infection. Herpes simplex virus (HSV) is well known as the causative agent of cold sores and genital herpes (reviewed in reference 1). When the virus infects tissues other than the oral or genital mucosa, such as ocular and brain tissues, much more serious diseases occur. Initial HSV-1 infections generally occur in toddlers and young children, and over two-thirds of the U.S. population is infected by adulthood (2). Primary infections may be asymptomatic or lead to the formation of characteristic blistering lesions (e.g., on or around the oral mucosa). The host immune system is usually able to clear the virus from infected epithelial tissues. However, HSV-1 establishes a latent infection in neuronal ganglia servicing the site of initial infection and persists there for the lifetime of the infected individual. HSV-1 may then reactivate from its latent state, which leads to recurrent viral replication in the epithelium and the formation of new lesions. Although currently available antiviral agents that act against HSV polymerase (Pol) can limit lytic replication in epithelial tissues, they are unable to eliminate latent HSV infections. Improvement of treatment for HSV disease relies heavily on a better understanding of cellular factors controlling HSV-1 replication in general.One such cellular factor is telomerase. Increased telomerase activity has been detected in cells infected with a variety of herpesviruses (3-11). There is evidence that HSV can mediate elevated telomerase activity during infection. Telomerase activity was found to be between 4 and 8 times greater in cells infected with a replication-defective mutant of HSV than in uninfected counterparts (3). This increase in activity was accompanied by enhanced telomerase reverse transcriptase (TERT) promoter activity.Previously, we determined that the levels of TERT could determine the sensitivity to HSV-dependent apoptosis (HDAP). Specifically, when tumor suppressor pathways were restored in HeLa cells, expression of TERT sensitized the cells to HDAP (12). This finding suggested that telomerase activation was sufficient to confer sensitivity to HDAP in HeLa cells. The initial goal of this study was to determine whether telomerase was necessary for HDAP. To do this, we utilized a small-molecule in...

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“…MST-312, a synthetic telomerase inhibitor of HSV-1, could directly inactivate HSV-1 through interfering with the life cycle of virions at 37 °C [ 25 ]. The structure of MST-312 shares moieties related to EGCG.…”

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“…46 Among them, MST-312 (Telomerase Inhibitor IX), a potent inhibitor of telomerase, has been reported to could suppress HSV replication at multiple steps of viral infection. 47 This may indicate that MST-312 could affect the tumor immune microenvironment by suppressing virus replication in virusrelated HCC. In a similar role, varenicline can prevent LPS-induced inflammatory response in RAW 264.7 Macrophages.…”

“…Except for VER‐155008, which is a proven HSP inhibitor, the other five drugs have not been reported to inhibit HSP90AA1 46 . Among them, MST‐312 (Telomerase Inhibitor IX), a potent inhibitor of telomerase, has been reported to could suppress HSV replication at multiple steps of viral infection 47 . This may indicate that MST‐312 could affect the tumor immune microenvironment by suppressing virus replication in virus‐related HCC.…”

Mice deficient in the mitochondrial branched-chain aminotransferase (BCATm) respond with delayed tumour growth to a challenge with EL-4 lymphoma

“…EL-4 cells treated with either 190 or 1140 µM leucine were simultaneously treated with 100 µM BAX-V5 or 100 µM negative control peptide (NCP) for 48 h. Alternatively, EL-4 cells were grown in the presence of 30 µM etoposide for 24 h. At the end of each treatment, live cells were incubated with 5 µg/ml Hoechst 33258 for 30 min at 37 °C, and fluorescent microscopy to monitor chromatin condensation as a readout of apoptosis was used as described. 32,33 The percentage of nuclei containing condensed chromatin was determined by dividing the number of brightly stained, small nuclei by the total number of nuclei. At least 100 nuclei were counted for each data point.…”