Dutia B M, Frame M C, Subak-Sharpe J H, Clark W N, Marsden H S
Nature. 1986;321(6068):439-41. doi: 10.1038/321439a0.
Ribonucleotide reductase is an essential enzyme for DNA synthesis in all prokaryotic and eukaryotic cells; it catalyses the reductive conversion of ribonucleotides to deoxyribonucleotides. Several herpesviruses including herpes simplex virus type 1 (HSV-1), HSV-2, pseudorabies virus (PRV), equine herpesvirus type 1 (EHV-1) and Epstein-Barr virus (EBV) have been found to induce novel ribonucleotide reductase activities. There is evidence that the HSV-1 ribonucleotide reductase activity is virus-encoded and essential for virus replication. This makes herpesvirus ribonucleotide reductases potential targets for antiviral chemotherapy. The HSV-1-encoded enzyme consists of two subunits: V136, the large subunit of relative molecular mass (Mr) 136,000 (136K) (RR1), which has been shown to be essential for enzyme activity, and V38, the small subunit (RR2) which forms a complex with the large subunit and is also likely to be essential for enzyme activity. Two particular features of the enzyme make it an attractive antiviral target. First, there is evidence for a common, highly conserved herpesvirus ribonucleotide reductase and second, the interaction between the large and small subunits may itself be exploitable. Here we identify a synthetic peptide which specifically inhibits the activity of virus-induced enzyme. We deduce that the mechanism of inhibition involves interference with the normal interaction between the two types of subunit.
核糖核苷酸还原酶是所有原核和真核细胞中DNA合成所必需的酶；它催化核糖核苷酸向脱氧核糖核苷酸的还原转化。已发现包括单纯疱疹病毒1型（HSV-1）、HSV-2、伪狂犬病病毒（PRV）、马疱疹病毒1型（EHV-1）和爱泼斯坦-巴尔病毒（EBV）在内的几种疱疹病毒可诱导新的核糖核苷酸还原酶活性。有证据表明HSV-1核糖核苷酸还原酶活性是病毒编码的，对病毒复制至关重要。这使得疱疹病毒核糖核苷酸还原酶成为抗病毒化疗的潜在靶点。HSV-1编码的酶由两个亚基组成：V136，相对分子质量（Mr）为136,000（136K）的大亚基（RR1），已证明其对酶活性至关重要；V38，小亚基（RR2），它与大亚基形成复合物，可能对酶活性也至关重要。该酶的两个特殊特性使其成为有吸引力的抗病毒靶点。首先，有证据表明存在一种共同的、高度保守的疱疹病毒核糖核苷酸还原酶；其次，大亚基和小亚基之间的相互作用本身可能是可利用的。在这里，我们鉴定出一种能特异性抑制病毒诱导酶活性的合成肽。我们推断抑制机制涉及干扰两种亚基之间的正常相互作用。
