Investigation of flexibility of neuraminidase 150-loop using tamiflu derivatives in influenza A viruses H1N1 and H5N1

被引：18

作者：

Zima, Vaclav ^{[1
,2
,3
]}

Albinana, Carlos Berenguer ^{[1
,2
,3
]}

Rojikova, Katerina ^{[2
,3
,4
]}

Pokorna, Jana ^{[2
,3
]}

Pachl, Petr ^{[2
,3
]}

Rezacova, Pavlina ^{[2
,3
,5
]}

Hudlicky, Jason ^{[1
,2
,3
]}

Navratil, Vaclav ^{[2
,3
]}

Majer, Pavel ^{[2
,3
]}

Konvalinka, Jan ^{[2
,3
,6
]}

Kozisek, Milan ^{[2
,3
]}

Machara, Ales ^{[1
,2
,3
]}

机构：

[1] Charles Univ Prague, Fac Sci, Dept Organ Chem, Hlavova 8, Prague 12800 2, Czech Republic

[2] Gilead Sci, Czech Acad Sci, Inst Organ Chem & Biochem, Flemingovo 2, Prague 16610 6, Czech Republic

[3] IOCB Res Ctr, Flemingovo 2, Prague 16610 6, Czech Republic

[4] Charles Univ Prague, Fac Med 1, Katerinska 1660-32, Prague 12108, Czech Republic

[5] Acad Sci Czech Republ, Inst Mol Genet, Videnska 1083, Prague 14000 4, Czech Republic

[6] Charles Univ Prague, Fac Sci, Dept Biochem, Hlavova 8, Prague 12800 2, Czech Republic

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 13期

关键词：

Influenza neuraminidase; Oseltamivir; Click chemistry; Crystal structure; STRUCTURAL-ANALYSIS; GLOBAL MORTALITY; 150; CAVITY; INHIBITORS; DESIGN; POTENT; OSELTAMIVIR; DISCOVERY; ZANAMIVIR; OUTBREAK;

D O I：

10.1016/j.bmc.2019.05.024

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：

This study focuses on design, synthesis and in vitro evaluation of inhibitory potency of two series of sialylmimetic that target an exosite ("150-cavity") adjacent to the active site of influenza neuraminidases from A/California/07/2009 (H1N1) pandemic strain and A/chicken/Nakorn-Patom/Thailand/CU-K2-2004 (H5N1). The structure-activity analysis as well as 3-D structure of the complex of parental compound with the pandemic neuraminidase p09N1 revealed high flexibility of the 150-cavity towards various modification of the neuraminidase inhibitors. Furthermore, our comparison of two methods for inhibition constant determination performed at slightly different pH values suggest that the experimental conditions of the measurement could dramatically influence the outcome of the analysis in the compound-dependent manner. Therefore, previously reported Ki values determined at non-physiological pH should be carefully scrutinized.

引用

页码：2935 / 2947

页数：13

共 62 条

[1] Exploitation of the Catalytic Site and 150 Cavity for Design of Influenza A Neuraminidase Inhibitors [J].