Mutations affecting the sensitivity of the influenza virus neuraminidase to 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid.
Mutations affecting the sensitivity of the influenza virus neuraminidase to 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid.
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影响流感病毒神经氨酸酶对 4-胍基-2,4-二脱氧-2,3-脱氢-N-乙酰神经氨酸敏感性的突变。
DOI：
10.1006/viro.1997.8810
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Kawaoka,Y
中科院分区：
文献类型：
--
作者：
Goto,H;Bethell,RC;Kawaoka,Y
4-guanidino-2,4-dideoxy-2,3-dehydro-N-乙酰神经氨酸 (4-guanidino-Neu5Ac2en) 通过胍基与酶底物结合袋中保守的 Glu 119 和 Glu 227 残基的相互作用，特异性抑制流感病毒神经氨酸酶 (NA)。为了了解流感病毒对 4-胍基-Neu5Ac2en 产生耐药性的机制，我们研究了流感病毒 NA 中氨基酸残基 119 和 227 的突变对该化合物和 NA 活性的影响。 NA基因从NWS-G70c病毒中克隆，并在氨基酸残基119或227的密码子处引入突变。所有13个在残基119处含有变化的突变体都被转运到细胞表面，尽管它们的表达水平为野生型的68.2%至91.3%。测试了保留至少 20% 野生型酶活性的突变 NA 对 4-胍基-Neu5Ac2en 的敏感性，发现对这种化合物的敏感性比野生型 NA 低七倍。相比之下，由残基 227 处的修饰定义的 13 个突变体中，只有 6 个被转运到细胞表面，并且这些 NA 缺乏实质性的酶活性（最多为野生型的 9%）。这些结果表明，在 4-胍基-Neu5Ac2en 的选择性压力下，只有有限数量的 Glu 119 和 Glu 227 突变产生了耐药性病毒，并且开发与 227 Glu 相互作用比 4-胍基-Neu5Ac2en 更强的化合物可能会进一步降低耐药病毒的可能性。
4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-guanidino-Neu5Ac2en) specifically inhibits the influenza virus neuraminidase (NA) through interaction of the guanidino group with conserved Glu 119 and Glu 227 residues in the substrate binding pocket of the enzyme. To understand the mechanism by which influenza viruses become resistant to 4-guanidino-Neu5Ac2en, we investigated mutations at amino acid residues 119 and 227 in the influenza virus NA for their effects on this compound and on NA activity. The NA gene was cloned from the NWS-G70c virus, and mutations were introduced at the codon for amino acid residue 119 or 227. All of the 13 mutants containing a change at residue 119 were transported to the cell surface, although their expression levels ranged from 68.2 to 91.3% of wild type. Mutant NAs that retained at least 20% of the wild-type enzymatic activity were tested for their sensitivity to 4-guanidino-Neu5Ac2en and found to be sevenfold less sensitive to this compound than was the wild-type NA. By contrast, only 6 of 13 mutants defined by modifications at residue 227 were transported to the cell surface, and those NAs lacked substantial enzymatic activity (9% of wild type, at most). These results suggest that only a limited number of resistant viruses arise through mutations at Glu 119 and Glu 227 under selective pressure from 4-guanidino-Neu5Ac2en and that the development of compounds which interact with 227 Glu more strongly than does 4-guanidino-Neu5Ac2en may reduce the likelihood of drug-resistant viruses still further.
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影响因子：
5.6
作者：
BOSSARTWHITAKER, P;CARSON, M;AIR, GM
通讯作者：
AIR, GM
影响因子：
5.4
作者：
Mitnaul, LJ;Castrucci, MR;Kawaoka, Y
通讯作者：
Kawaoka, Y
与表达的野生型蛋白相比，流感神经氨酸酶定点突变体的酶活性丧失。
影响因子：
3.7
作者：
Lentz,MR;Air,GM
通讯作者：
Air,GM
A/WSN/33 流感病毒四种温度敏感突变体神经氨酸酶基因缺陷的鉴定。
影响因子：
3.7
作者：
Bos,TJ;Nayak,DP
通讯作者：
Nayak,DP
GG167（4-guanidino-2,4-dideoxy-2,3-deHydro-N-乙酰神经氨酸）是雪貂流感病毒的有效抑制剂
影响因子：
4.9
作者：
D. M. Ryan;Julia Ticehurst;M. Dempsey
通讯作者：
M. Dempsey