Inhibitor selectivity of a new class of oseltamivir analogs against viral neuraminidase over human neuraminidase enzymes

被引:36
作者
Albohy, Amgad [1 ]
Mohan, Sankar [2 ]
Zheng, Ruixiang Blake [1 ]
Pinto, B. Mario [2 ]
Cairo, Christopher W. [1 ]
机构
[1] Univ Alberta, Dept Chem, Alberta Ingenu Ctr Carbohydrate Sci, Edmonton, AB T6G 2G2, Canada
[2] Simon Fraser Univ, Dept Chem, Burnaby, BC V5A 1S6, Canada
基金
加拿大创新基金会; 加拿大自然科学与工程研究理事会;
关键词
Viral neuraminidase; Human neuraminidase; Sialidase; Antiviral; Glycosidase; Enzyme inhibitor; NEU3; NEU4; NEU2; NEU1; Oseltamivir; Zanamivir; INFLUENZA-VIRUS NEURAMINIDASE; HUMAN CYTOSOLIC SIALIDASE; SUBSTRATE RECOGNITION; TRANSGENIC MICE; DRUG DESIGN; ACID; NEU3; SIALIDOSIS; MUTATIONS; BINDING;
D O I
10.1016/j.bmc.2011.03.039
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The viral neuraminidase enzyme is an established target for anti-influenza pharmaceuticals. However, viral neuraminidase inhibitors could have off-target effects due to interactions with native human neuraminidase enzymes. We report the activity of a series of known inhibitors of the influenza group-1 neuraminidase enzyme (N1 subtype) against recombinant forms of the human neuraminidase enzymes NEU3 and NEU4. These inhibitors were designed to take advantage of an additional enzyme pocket (known as the 150-cavity) near the catalytic site of certain viral neuraminidase subtypes (N1, N4 and N8). We find that these modified derivatives have minimal activity against the human enzymes, NEU3 and NEU4. Two compounds show moderate activity against NEU3, possibly due to alternative binding modes available to these structures. Our results reinforce that recognition of the glycerol side-chain is distinct between the viral and human NEU enzymes, and provide experimental support for improving the selectivity of viral neuraminidase inhibitors by exploiting the 150-cavity found in certain subtypes of viral neuraminidases. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2817 / 2822
页数:6
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