Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations

Viktoriya S. Sidorenko; Ira Cohen; Kunchok Dorjee; Conceição A. Minetti; David P. Remeta; Junyuan Gao; Irina Potapova; Hong Zhan Wang; Janet Hearing; Wan Yi Yen; Hwan Keun Kim; Keiji Hashimoto; Masaaki Moriya; Kathleen G. Dickman; Xingyu Yin; Miguel Garcia-Diaz; Rajesh Chennamshetti; Radha Bonala; Francis Johnson; Amanda L. Waldeck; Ramesh Gupta; Chaoping Li; Kenneth J. Breslauer; Arthur P. Grollman; Thomas A. Rosenquist

doi:10.1016/j.virusres.2024.199322

Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations

Viktoriya S. Sidorenko, Ira Cohen, Kunchok Dorjee, Conceição A. Minetti, David P. Remeta, Junyuan Gao, Irina Potapova, Hong Zhan Wang, Janet Hearing, Wan Yi Yen, Hwan Keun Kim, Keiji Hashimoto, Masaaki Moriya, Kathleen G. Dickman, Xingyu Yin, Miguel Garcia-Diaz, Rajesh Chennamshetti, Radha Bonala, Francis Johnson, Amanda L. WaldeckRamesh Gupta, Chaoping Li, Kenneth J. Breslauer, Arthur P. Grollman, Thomas A. Rosenquist

School of Arts and Sciences, Chemistry & Chemical Biology

Rutgers, The State University

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

Abstract

The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC₅₀ ∼ 50–100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC₅₀ ∼ 40–60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

Original language	American English
Article number	199322
Journal	Virus Research
Volume	341
DOIs	https://doi.org/10.1016/j.virusres.2024.199322
State	Published - Mar 2024

ASJC Scopus subject areas

Virology
Infectious Diseases
Cancer Research

Keywords

Antiviral
Coronoviruses
Dehydroemetine
Emetine
SARS-CoV-2

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10.1016/j.virusres.2024.199322

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Sidorenko, V. S., Cohen, I., Dorjee, K., Minetti, C. A., Remeta, D. P., Gao, J., Potapova, I., Wang, H. Z., Hearing, J., Yen, W. Y., Kim, H. K., Hashimoto, K., Moriya, M., Dickman, K. G., Yin, X., Garcia-Diaz, M., Chennamshetti, R., Bonala, R., Johnson, F., ... Rosenquist, T. A. (2024). Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations. Virus Research, 341, Article 199322. https://doi.org/10.1016/j.virusres.2024.199322

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title = "Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations",

abstract = "The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50–100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40–60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.",

keywords = "Antiviral, Coronoviruses, Dehydroemetine, Emetine, SARS-CoV-2",

author = "Sidorenko, {Viktoriya S.} and Ira Cohen and Kunchok Dorjee and Minetti, {Concei{\c c}{\~a}o A.} and Remeta, {David P.} and Junyuan Gao and Irina Potapova and Wang, {Hong Zhan} and Janet Hearing and Yen, {Wan Yi} and Kim, {Hwan Keun} and Keiji Hashimoto and Masaaki Moriya and Dickman, {Kathleen G.} and Xingyu Yin and Miguel Garcia-Diaz and Rajesh Chennamshetti and Radha Bonala and Francis Johnson and Waldeck, {Amanda L.} and Ramesh Gupta and Chaoping Li and Breslauer, {Kenneth J.} and Grollman, {Arthur P.} and Rosenquist, {Thomas A.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = mar,

doi = "10.1016/j.virusres.2024.199322",

language = "American English",

volume = "341",

journal = "Virus Research",

issn = "0168-1702",

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Sidorenko, VS, Cohen, I, Dorjee, K, Minetti, CA , Remeta, DP, Gao, J, Potapova, I, Wang, HZ, Hearing, J, Yen, WY, Kim, HK, Hashimoto, K, Moriya, M, Dickman, KG, Yin, X, Garcia-Diaz, M, Chennamshetti, R, Bonala, R, Johnson, F, Waldeck, AL, Gupta, R, Li, C, Breslauer, KJ, Grollman, AP & Rosenquist, TA 2024, 'Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations', Virus Research, vol. 341, 199322. https://doi.org/10.1016/j.virusres.2024.199322

TY - JOUR

T1 - Mechanisms of antiviral action and toxicities of ipecac alkaloids

T2 - Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations

AU - Sidorenko, Viktoriya S.

AU - Cohen, Ira

AU - Dorjee, Kunchok

AU - Minetti, Conceição A.

AU - Remeta, David P.

AU - Gao, Junyuan

AU - Potapova, Irina

AU - Wang, Hong Zhan

AU - Hearing, Janet

AU - Yen, Wan Yi

AU - Kim, Hwan Keun

AU - Hashimoto, Keiji

AU - Moriya, Masaaki

AU - Dickman, Kathleen G.

AU - Yin, Xingyu

AU - Garcia-Diaz, Miguel

AU - Chennamshetti, Rajesh

AU - Bonala, Radha

AU - Johnson, Francis

AU - Waldeck, Amanda L.

AU - Gupta, Ramesh

AU - Li, Chaoping

AU - Breslauer, Kenneth J.

AU - Grollman, Arthur P.

AU - Rosenquist, Thomas A.

PY - 2024/3

Y1 - 2024/3

N2 - The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50–100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40–60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

AB - The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50–100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40–60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

KW - Antiviral

KW - Coronoviruses

KW - Dehydroemetine

KW - Emetine

KW - SARS-CoV-2

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U2 - 10.1016/j.virusres.2024.199322

DO - 10.1016/j.virusres.2024.199322

M3 - Article

C2 - 38228190

SN - 0168-1702

VL - 341

JO - Virus Research

JF - Virus Research

M1 - 199322

ER -

Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations

Abstract

ASJC Scopus subject areas

Keywords

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