Signal amplification by reversible exchange for COVID-19 antiviral drug candidates

Hye Jin Jeong,Heelim Chae,Sein Min,Gunwoo Lee,Keunhong Jeong,Sung Keon Namgoong,Sarah Kim

doi:10.1038/s41598-020-71282-6

Hye Jin Jeong, Heelim Chae + Show 5 more

Open Access

https://doi.org/10.1038/s41598-020-71282-6

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Abstract

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.

Highlights

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19)
Methanol-d4(CD3OD, 99.8 atom % D, Eurisotop) was used in the form it was obtained. 1H nuclear magnetic resonance (NMR) spectra used for the characterization of favipiravir, chloroquine, hydroxychloroquine, lopinavir, and ritonavir were acquired on a Bruker Avance Ш NMR spectrometer operating at a 1H resonance frequency of 300 MHz, and were referenced to the residual CH3 peak of CD3OD (δ = 3.31)
To determine the exact integral of the signal through the same chemical shift region, the solvent peak was compared. Antiviral drugs, such as chloroquine, hydroxychloroquine, ritonavir, lopinavir, and favipiravir have been investigated as drug candidates in response to the COVID-19 pandemic situation

Summary

Introduction

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine (7-chloro-4-(4-diethylamino-1-methylbutylamino)-quinoline) and hydroxychloroquine (2-[4-[(7-chloroquinolin-4-yl)amino]pentylethylamino]ethanol), which have been in clinical usage for the last seventy years, are drugs for the treatment of autoimmune disease, they are used as antimalarial drugs These compounds have recently been reported as potential broad-spectrum antiviral drugs for COVID-195; their benefits against COVID-19 are controversial, with no evident effect on hospitalized patients[6]. Ritonavir/lopinavir (1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate/ (2S)-N-[(2S,4S,5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino] -4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl2-(2-oxo-1,3-diazinan-1-yl)butanamide), the combination drug marketed as Kaletra, is a relatively new medication for the treatment and prevention of HIV This compound has been suggested as a potential drug candidate against COVID-19 due to its role as a proteinase inhibitor in association with the polyprotein processing of the c oronavirus[11,12]. Favipiravir (5-fluoro-2-oxo-1H-pyrazine-3-carboxamide), which has been approved in Japan for the treatment of influenza since 201416,17, has shown effectiveness in accelerating viral clearance in Chinese trials of hundreds of p atients[18]

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