Sanchez Maria Dulfary, Ochoa Augusto C, Foster Timothy P
Department of Microbiology, Immunology, and Parasitology, School of Medicine, Louisiana State University Health Sciences Center, USA; Department of Pediatrics, School of Medicine, Louisiana State University Health Sciences Center, USA; The Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, USA.
Department of Pediatrics, School of Medicine, Louisiana State University Health Sciences Center, USA; The Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, USA; The Louisiana Vaccine Center, New Orleans, LA, 70112, USA.
Antiviral Res. 2016 Aug;132:13-25. doi: 10.1016/j.antiviral.2016.05.009. Epub 2016 May 15.
Since their inception five decades ago, most antivirals have been engineered to disrupt a single viral protein or process that is essential for viral replication. This approach has limited the overall therapeutic effectiveness and applicability of current antivirals due to restricted viral specificity, a propensity for development of drug resistance, and an inability to control deleterious host-mediated inflammation. As obligate intracellular parasites, viruses are reliant on host metabolism and macromolecular synthesis pathways. Of these biosynthetic processes, many viruses, including Herpes simplex viruses (HSV), are absolutely dependent on the bioavailability of arginine, a non-essential amino acid that is critical for many physiological and pathophysiological processes associated with either facilitating viral replication or progression of disease. To assess if targeting host arginine-associated metabolic pathways would inhibit HSV replication, a pegylated recombinant human Arginase I (peg-ArgI) was generated and its in vitro anti-herpetic activity was evaluated. Cells continuously treated with peg-ArgI for over 48 h exhibited no signs of cytotoxicity or loss of cell viability. The antiviral activity of peg-ArgI displayed a classical dose-response curve with IC50's in the sub-nanomolar range. peg-ArgI potently inhibited HSV-1 and HSV-2 viral replication, infectious virus production, cell-to-cell spread/transmission and virus-mediated cytopathic effects. Not unexpectedly given its host-targeted mechanism of action, peg-ArgI showed similar effectiveness at controlling replication of single and multidrug resistant HSV-1 mutants. These findings illustrate that targeting host arginine-associated metabolic pathways is an effective means of controlling viral replicative processes. Further exploration into the breadth of viruses inhibited by peg-ArgI, as well as the ability of peg-ArgI to suppress arginine-associated virus-mediated pathophysiological disease processes is warranted.
自五十年前问世以来，大多数抗病毒药物的设计初衷都是干扰单一病毒蛋白或对病毒复制至关重要的过程。由于病毒特异性受限、存在耐药性发展倾向以及无法控制有害的宿主介导的炎症，这种方法限制了当前抗病毒药物的整体治疗效果和适用性。作为专性细胞内寄生虫，病毒依赖于宿主代谢和大分子合成途径。在这些生物合成过程中，许多病毒，包括单纯疱疹病毒（HSV），绝对依赖于精氨酸的生物可利用性，精氨酸是一种非必需氨基酸，对许多与促进病毒复制或疾病进展相关的生理和病理生理过程至关重要。为了评估靶向宿主精氨酸相关代谢途径是否会抑制HSV复制，制备了聚乙二醇化重组人精氨酸酶I（peg-ArgI）并评估了其体外抗疱疹活性。连续用peg-ArgI处理超过48小时的细胞未表现出细胞毒性迹象或细胞活力丧失。peg-ArgI的抗病毒活性呈现出典型的剂量反应曲线，IC50处于亚纳摩尔范围。peg-ArgI有效抑制HSV-1和HSV-2病毒复制、感染性病毒产生、细胞间传播/传递以及病毒介导的细胞病变效应。鉴于其靶向宿主的作用机制，peg-ArgI在控制单药和多药耐药HSV-1突变体的复制方面表现出相似的有效性也就不足为奇了。这些发现表明，靶向宿主精氨酸相关代谢途径是控制病毒复制过程的有效手段。有必要进一步探索peg-ArgI抑制病毒的广度，以及peg-ArgI抑制精氨酸相关病毒介导的病理生理疾病过程的能力。
