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二价抑制剂混合抑制神经氨酸酶和血凝素预防甲型流感病毒感染。

Preventing Influenza A Virus Infection by Mixed Inhibition of Neuraminidase and Hemagglutinin by Divalent Inhibitors.

机构信息

Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, Utrecht NL-3508 TB, The Netherlands.

Section Virology, Division Infectious Diseases and Immunology, Faculty Veterinary Medicine, Utrecht University, Utrecht NL-3508 TB, The Netherlands.

出版信息

J Med Chem. 2022 May 26;65(10):7312-7323. doi: 10.1021/acs.jmedchem.2c00319. Epub 2022 May 12.

DOI:10.1021/acs.jmedchem.2c00319
PMID:35549211
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9150099/
Abstract

Divalent inhibitors of the neuraminidase enzyme (NA) of the Influenza A virus were synthesized with vastly different spacers. The spacers varied from 14 to 56 atoms and were relatively rigid by way of the building blocks and their connection by CuAAC. As the ligand for these constructs, a Δ-β-d-glucoronide was used, which can be prepared form -acetyl glucosamine. This ligand showed good NA inhibitory potency but with room for improvement by multivalency enhancement. The synthesized compounds showed modest potency enhancement in NA activity assays but a sizeable potency increase in a 4-day cytopathic effect assay. The demonstration that the compounds can also inhibit hemagglutinin in addition to NA may be the cause of the enhancement.

摘要

二价流感 A 病毒神经氨酸酶（NA）抑制剂的合成使用了具有极大差异的间隔基。间隔基的原子数从 14 到 56 不等，通过构建块及其通过 CuAAC 的连接，间隔基具有相对刚性。作为这些结构的配体，使用了 Δ-β-d-葡糖苷酸，它可以从 -乙酰葡萄糖胺制备得到。该配体显示出良好的 NA 抑制效力，但通过多价增强仍有改进的空间。合成的化合物在 NA 活性测定中显示出适度的效力增强，但在 4 天细胞病变效应测定中显示出相当大的效力增加。化合物除了 NA 之外还可以抑制血凝素的事实可能是增强的原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/a604f41e7845/jm2c00319_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/249c76b57061/jm2c00319_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/1323ebbf5bec/jm2c00319_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/347a4b815134/jm2c00319_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/1868ef048905/jm2c00319_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/4fbc98071486/jm2c00319_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/5eb97975b58f/jm2c00319_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/82436f34b49c/jm2c00319_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/a604f41e7845/jm2c00319_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/249c76b57061/jm2c00319_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/1323ebbf5bec/jm2c00319_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/347a4b815134/jm2c00319_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/1868ef048905/jm2c00319_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/4fbc98071486/jm2c00319_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/5eb97975b58f/jm2c00319_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/82436f34b49c/jm2c00319_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7034/9150099/a604f41e7845/jm2c00319_0006.jpg

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