Notterman, Daniel A.Marcovsky, Ellie2025-12-082025-12-082025-04https://theses-dissertations.princeton.edu/handle/88435/dsp011v53k1469Cytomegalovirus (CMV) remains a significant global health concern, particularly in immunocompromised individuals and in its propensity to produce serious congenital infections and birth defects. Telomerase, a ribonucleoprotein complex that maintains telomere integrity, has emerged as a novel target in antiviral therapy due to its regulatory role in cell proliferation and virus-host interactions. Prior work from our laboratory (Cavanaugh, et al. 2025) has established that inhibition of host telomerase in human cell cultures is viricidal; this suggests an entirely new approach to anti-viral therapy. This thesis aims to address the engineering challenge of developing a robust murine model to study telomerase inhibition as a treatment for murine cytomegalovirus (MCMV) infection. The first aim is to validate murine cells as a biologically relevant system by determining whether MCMV upregulates telomerase activity, and whether pharmacologic inhibition of telomerase suppresses viral gene expression. This was accomplished through TRAP assays, qPCR of mTERT and IE1 expression, and cytotoxicity profiling of telomerase inhibitors. The second aim is to evaluate and compare the efficacy of four telomerase-inhibiting compounds, MST-312, BIBR-1532, BRACO-19, and RHPS4, by assessing their impact on both telomerase activity and viral gene expression in infected MEFs. This includes determination of LD50 values, quantification of mTERT repression, and analysis of immediate early viral gene (IE1) expression. By quantifying the degree of viral suppression following telomerase inhibition, this study identifies promising candidates for further preclinical testing. Ultimately, this work lays the foundation for a murine model of CMV suppression via telomerase inhibition and offers insights into the translational potential of telomerase-targeting antivirals. It bridges virology, cellular biology, and therapeutic engineering in pursuit of innovative antiviral strategies.en-USPrinceton University Senior Theses