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Abstract：
The non-structural 4B (NS4B) protein of hepatitis C virus (HCV) is a hydrophobic protein implicated recently in the formation of membranous web, a platform for the formation of replication complex and thus is potential target for antivirals. The CLC main workbench was used to generate genotype-specific consensus sequence, global consensus sequence and a representative phylogenetic tree from non-structural 4 B (NS4B) protein sequences of seven different HCV genotypes reported from all over the world. The C-terminal domain (CTD) of NS4B protein especially the residues involved in interaction with ER membrane were found to be highly conserved. Other residues found to be highly conserved across all HCV genotypes included; 5 aromatic residues of N-terminal domain (NTD) (F49, W50, W55, F57, and Y63), 3 hydrophobic leucine residues (L237, L240, L245), and 2 positively charged residues of CTD (R248 and H250), dimerization motif of transmembrane domain 3 (TMD3) (G143YGAG147) and its surrounding residues (F118 and F155) and TMD1 Ser/Thr cluster residues (T87, S88 and T95) involved in the hydrogen (H) bond interactions. In short, amino acids of NTD, TMD and CTD domains involved in the membrane association/anchoring of NS4B and formation of membranous web are highly conserved and can serve as potential targets for antivirals and peptide vaccines. These conserved residues formed the basis for the development of five short peptides proposed to serve as potential therapeutic target. The phylogenetic analysis was particularly interesting for NS4B sequences of 3a Pakistani isolates. The high degree of variability prevented the clustering of Pakistani isolates with other sequences in phylogenetic tree, revealing geographical disparity.
摘要：
丙型肝炎病毒（HCV）的非结构4B（NS4B）蛋白是最近参与膜网形成的疏水性蛋白，复制复合物形成的平台，因此是抗病毒药物的潜在靶标。CLC主工作台用于生成基因型特异性共有序列，全球共有序列和来自来自世界各地报道的7种不同HCV基因型的非结构4B（NS4B）蛋白序列的代表性系统发育树。NS4B蛋白的C端结构域（CTD），尤其是与ER膜相互作用的残基被发现是高度保守的。发现在所有HCV基因型中高度保守的其他残基包括：N末端结构域（NTD）的5个芳香族残基（F49，W50，W55，F57和Y63），3个疏水亮氨酸残基（L237，L240，L245），和2个带正电荷的CTD残基（R248和H250），跨膜结构域3（TMD3）（G143YGAG147）及其周围残基（F118和F155）和TMD1Ser/Thr簇残基（T87，S88和T95）的二聚化基序参与氢（H）键相互作用。总之,NTD的氨基酸，参与NS4B的膜结合/锚定和膜网形成的TMD和CTD结构域是高度保守的,并且可以用作抗病毒剂和肽疫苗的潜在靶标。这些保守的残基构成了开发五种被提议作为潜在治疗靶标的短肽的基础。对于3a巴基斯坦分离株的NS4B序列，系统发育分析特别有趣。高度的变异性阻止了巴基斯坦分离株与系统发育树中其他序列的聚类，揭示地理差异。
