Liu Shenping, Knafels John D, Chang Jeanne S, Waszak Gregory A, Baldwin Eric T, Deibel Martin R, Thomsen Darrell R, Homa Fred L, Wells Peter A, Tory Monica C, Poorman Roger A, Gao Hua, Qiu Xiayang, Seddon Andrew P
Exploratory Medicinal Sciences, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
J Biol Chem. 2006 Jun 30;281(26):18193-200. doi: 10.1074/jbc.M602414200. Epub 2006 Apr 24.
Herpesviruses are the second leading cause of human viral diseases. Herpes Simplex Virus types 1 and 2 and Varicella-zoster virus produce neurotropic infections such as cutaneous and genital herpes, chickenpox, and shingles. Infections of a lymphotropic nature are caused by cytomegalovirus, HSV-6, HSV-7, and Epstein-Barr virus producing lymphoma, carcinoma, and congenital abnormalities. Yet another series of serious health problems are posed by infections in immunocompromised individuals. Common therapies for herpes viral infections employ nucleoside analogs, such as Acyclovir, and target the viral DNA polymerase, essential for viral DNA replication. Although clinically useful, this class of drugs exhibits a narrow antiviral spectrum, and resistance to these agents is an emerging problem for disease management. A better understanding of herpes virus replication will help the development of new safe and effective broad spectrum anti-herpetic drugs that fill an unmet need. Here, we present the first crystal structure of a herpesvirus polymerase, the Herpes Simplex Virus type 1 DNA polymerase, at 2.7 A resolution. The structural similarity of this polymerase to other alpha polymerases has allowed us to construct high confidence models of a replication complex of the polymerase and of Acyclovir as a DNA chain terminator. We propose a novel inhibition mechanism in which a representative of a series of non-nucleosidic viral polymerase inhibitors, the 4-oxo-dihydroquinolines, binds at the polymerase active site interacting non-covalently with both the polymerase and the DNA duplex.
疱疹病毒是人类病毒性疾病的第二大主要病因。1型和2型单纯疱疹病毒以及水痘带状疱疹病毒会引发嗜神经性感染，如皮肤和生殖器疱疹、水痘及带状疱疹。嗜淋巴细胞性感染由巨细胞病毒、HSV - 6、HSV - 7和爱泼斯坦 - 巴尔病毒引起，可导致淋巴瘤、癌症和先天性异常。免疫功能低下个体的感染还会引发一系列其他严重的健康问题。疱疹病毒感染的常用治疗方法使用核苷类似物，如阿昔洛韦，其作用靶点是病毒DNA聚合酶，这对病毒DNA复制至关重要。尽管这类药物在临床上有用，但抗病毒谱较窄，而且对这些药物产生耐药性正成为疾病治疗中一个新出现的问题。更好地了解疱疹病毒复制将有助于开发新的安全有效的广谱抗疱疹药物，以满足尚未满足的需求。在此，我们展示了疱疹病毒聚合酶——1型单纯疱疹病毒DNA聚合酶——分辨率为2.7埃的首个晶体结构。该聚合酶与其他α聚合酶的结构相似性使我们能够构建该聚合酶复制复合体以及作为DNA链终止剂的阿昔洛韦的高可信度模型。我们提出了一种新的抑制机制，其中一系列非核苷类病毒聚合酶抑制剂的代表——4 - 氧代 - 二氢喹啉，在聚合酶活性位点结合，与聚合酶和DNA双链非共价相互作用。
