Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Drake University, Des Moines, IA, 50311, USA.
Department of Microbiology and Immunology, College of Osteopathic Medicine, Des Moines University, Des Moines, IA, 50312, USA.
Antiviral Res. 2021 Mar;187:105018. doi: 10.1016/j.antiviral.2021.105018. Epub 2021 Jan 18.
MBX-2168 has a mechanism of action similar to that of acyclovir (ACV) and ganciclovir (GCV), but two unique steps differentiate this drug from ACV/GCV. First, MBX-2168 is, at least partially, phosphorylated by the endogenous cellular kinase TAOK3 to a monophosphate. The second involves the removal of a moiety at the 6-position of MBX-2168-MP by adenosine deaminase like protein-1 (ADAL-1). It has been previously demonstrated that co-incubation with pentostatin (dCF), an ADAL-1 inhibitor, antagonizes the anti-viral activity of MBX-2168. We therefore hypothesize that inhibiting ADAL-1 results in a reduction of active compound produced in virus-infected cells. To test this, we examined the effect dCF has on the conversion of MBX-2168 to a triphosphate in HSV-1 and HCMV-infected cells. Our results demonstrate incubation of MBX-2168 alone or with dCF in HCMV-infected cells resulted in 53.1 ± 0.7 and 39.4 ± 1.5 pmol triphosphate/10 cells at 120 h, respectively. Incubation of MBX-2168 alone or with dCF in Vero cells resulted in 12.8 ± 0.1 and 6.7 ± 0.7 pmol triphosphate/10 cells at 24 h, respectively. HSV-1-infected Vero cells demonstrated no statistical difference in triphosphate accumulation at 24 h (13.1 ± 0.3 pmol triphosphate/10 cells). As expected, incubation with dCF resulted in the accumulation of MBX-2168-MP in both HFF (9.8 ± 0.9 pmol MBX-2168-MP/10 cells at 120 h) and Vero cells (4.7 ± 0.3 pmol MBX-2168-MP/10 cells at 24 h) while no detectable levels of monophosphate were observed in cultures not incubated with dCF. We conclude that dCF antagonizes the anti-viral effect of MBX-2168 by inhibiting the production of triphosphate, the active compound.
MBX-2168 的作用机制与阿昔洛韦 (ACV) 和更昔洛韦 (GCV) 相似，但有两个独特的步骤使该药物有别于 ACV/GCV。首先，MBX-2168 至少部分被内源性细胞激酶 TAOK3 磷酸化为单磷酸。第二个涉及通过腺苷脱氨酶样蛋白-1 (ADAL-1) 从 MBX-2168-MP 的 6 位上去除部分。先前已经证明，与戊糖苷 (dCF) 共同孵育，一种 ADAL-1 抑制剂，拮抗 MBX-2168 的抗病毒活性。因此，我们假设抑制 ADAL-1 会导致病毒感染细胞中产生的活性化合物减少。为了验证这一点，我们研究了 dCF 对 HSV-1 和 HCMV 感染细胞中 MBX-2168 转化为三磷酸的影响。我们的结果表明，在 HCMV 感染的细胞中单独孵育 MBX-2168 或与 dCF 孵育分别导致 120 小时时 53.1 ± 0.7 和 39.4 ± 1.5 pmol 三磷酸/10 个细胞，而在 Vero 细胞中单独孵育 MBX-2168 或与 dCF 孵育分别导致 24 小时时 12.8 ± 0.1 和 6.7 ± 0.7 pmol 三磷酸/10 个细胞。HSV-1 感染的 Vero 细胞在 24 小时时三磷酸积累没有统计学差异（13.1 ± 0.3 pmol 三磷酸/10 个细胞）。正如预期的那样，用 dCF 孵育会导致 MBX-2168-MP 在 HFF（120 小时时 9.8 ± 0.9 pmol MBX-2168-MP/10 个细胞）和 Vero 细胞（24 小时时 4.7 ± 0.3 pmol MBX-2168-MP/10 个细胞）中积累，而在用 dCF 孵育的培养物中未检测到单磷酸。我们得出结论，dCF 通过抑制三磷酸的产生，即活性化合物，拮抗 MBX-2168 的抗病毒作用。
