Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited

Antonios Drakopoulos; Christina Tzitzoglaki; Chulong Ma; Kathrin Freudenberger; Anja Hoffmann; Yanmei Hu; Günter Gauglitz; Michaela Schmidtke; Jun Wang; Antonios Kolocouris

doi:10.1021/acsmedchemlett.6b00311

Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited

Antonios Drakopoulos
, Christina Tzitzoglaki
, Chulong Ma
, Kathrin Freudenberger
, Anja Hoffmann
, Yanmei Hu
, Günter Gauglitz
, Michaela Schmidtke
, Jun Wang
, Antonios Kolocouris

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.

Original language	English (US)
Pages (from-to)	145-150
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	2
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00311
State	Published - Feb 9 2017

Keywords

Bennett’s acceptance ratio
Rimantadine enantiomers
antiviral assay
electrophysiology
free energy perturbation
influenza M2 pore
isothermal titration calorimetry
membrane protein
synthesis

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.6b00311

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title = "Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited",

abstract = "Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.",

keywords = "Bennett{\textquoteright}s acceptance ratio, Rimantadine enantiomers, antiviral assay, electrophysiology, free energy perturbation, influenza M2 pore, isothermal titration calorimetry, membrane protein, synthesis",

author = "Antonios Drakopoulos and Christina Tzitzoglaki and Chulong Ma and Kathrin Freudenberger and Anja Hoffmann and Yanmei Hu and G{\"u}nter Gauglitz and Michaela Schmidtke and Jun Wang and Antonios Kolocouris",

note = "Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

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doi = "10.1021/acsmedchemlett.6b00311",

language = "English (US)",

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T1 - Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited

AU - Drakopoulos, Antonios

AU - Tzitzoglaki, Christina

AU - Ma, Chulong

AU - Freudenberger, Kathrin

AU - Hoffmann, Anja

AU - Hu, Yanmei

AU - Gauglitz, Günter

AU - Schmidtke, Michaela

AU - Wang, Jun

AU - Kolocouris, Antonios

PY - 2017/2/9

Y1 - 2017/2/9

N2 - Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.

AB - Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.

KW - Bennett’s acceptance ratio

KW - Rimantadine enantiomers

KW - antiviral assay

KW - electrophysiology

KW - free energy perturbation

KW - influenza M2 pore

KW - isothermal titration calorimetry

KW - membrane protein

KW - synthesis

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UR - https://www.scopus.com/pages/publications/85013828925#tab=citedBy

U2 - 10.1021/acsmedchemlett.6b00311

DO - 10.1021/acsmedchemlett.6b00311

M3 - Article

AN - SCOPUS:85013828925

SN - 1948-5875

VL - 8

SP - 145

EP - 150

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 2

ER -

Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited

Abstract

Keywords

ASJC Scopus subject areas

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