Pentostatin antagonizes the antiviral activity of MBX-2168 by inhibiting the biosynthesis of the active compound.
Pentostatin antagonizes the antiviral activity of MBX-2168 by inhibiting the biosynthesis of the active compound.
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DOI：
10.1016/j.antiviral.2021.105018
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发表时间：
2021-03
影响因子：
7.6
通讯作者：
Gentry BG
中科院分区：
文献类型：
--
作者：
Hagen NR;Nguyen ML;Williams JD;Bowlin TL;Gentry BG
MBX-2168的作用机制类似于阿昔洛韦（ACV）和更昔洛韦（GCV），但有两个独特的步骤将其与ACV/GCV区分开来。首先，MBX-2168至少部分被内源性细胞激酶TAOK3磷酸化为单磷酸盐。第二种是腺苷脱氨酶样蛋白-1 （ADAL-1）去除MBX-2168-MP的6位片段。先前已经证明，与戊司他汀（一种ADAL-1抑制剂）共孵育可拮抗MBX-2168的抗病毒活性。因此，我们假设抑制ADAL-1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，我们检测了dCF对HSV-1和hcmv感染细胞中MBX-2168转化为三磷酸盐的影响。我们的研究结果表明，MBX-2168单独或与dCF在hcmv感染的细胞中孵育120小时，分别产生53.1±0.7和39.4±1.5 pmol三磷酸/106个细胞。MBX-2168单独或与dCF在Vero细胞中孵育24小时，分别产生12.8±0.1和6.7±0.7 pmol三磷酸/106个细胞。hsv -1感染的Vero细胞在24小时内的三磷酸积累无统计学差异（13.1±0.3 pmol triphosphate/106个细胞）。正如预期的那样，与dCF孵育导致MBX-2168-MP在HFF（120小时9.8±0.9 pmol MBX-2168-MP/106细胞）和Vero细胞（24小时4.7±0.3 pmol MBX-2168-MP/106细胞）中积累，而在未与dCF孵育的培养物中未观察到可检测到的单磷酸盐水平。我们得出结论，dCF通过抑制活性化合物三磷酸的产生来拮抗MBX-2168的抗病毒作用。
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/106 cells at 120 hours, 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/106 cells at 24 hours, respectively. HSV-1-infected Vero cells demonstrated no statistical difference in triphosphate accumulation at 24 hours (13.1±0.3 pmol triphosphate/106 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/106 cells at 120 hours) and Vero cells (4.7±0.3 pmol MBX-2168-MP/106 cells at 24 hours) 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.
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