In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases

Author(s)

Eberle, Raphael J. ^{[1, 2]} ; Olivier, Danilo S. ^[3] ; Pacca, Carolina C. ^{[4, 5]} ; Avilla, Clarita M. S. ^[5] ; Nogueira, Mauricio L. ^[6] ; Amaral, Marcos S. ^[7] ; Willbold, Dieter ^{[8, 2, 9]} ; Arni, Raghuvir K. ^[1] ; Coronado, Monika A. ^{[1, 2]}

Affiliation

^[1] Univ Estadual Paulista UNESP, Multiuser Ctr Biomol Innovat, Inst Biociencias Letras & Ciencias Exatas Ibilce, Dept Phys, Sao Jose Do Rio Preto, SP - Brazil

^[2] Forschungszentrum Julich, Inst Biol Informat Proc IBI 7 Struct Biochem, Julich - Germany

^[3] Fed Univ Tocantins, Araguaina, TO - Brazil

^[4] FACERES Med Sch, Sao Jose Do Rio Preto - Brazil

^[5] Univ Estadual Paulista UNESP, Inst Biociencias Letras & Ciencias Exatas Ibilce, Sao Jose Do Rio Preto, SP - Brazil

^[6] Fac Med Sao Jose Do Rio Preto FAMERP, Sao Jose Do Rio Preto - Brazil

^[7] Univ Fed Mato Grosso do Sul, Inst Phys, Campo Grande, MS - Brazil

^[8] Heinrich Heine Univ Dusseldorf, Inst Phys Biol, Univ Str, Dusseldorf - Germany

^[9] Forchungszentrum Julich, JuStruct Julich Ctr Struct Biol, Julich - Germany

• Document type: Journal article
• Source: PLoS One; v. 16, n. 3 MAR 4 2021.
• Web of Science Citations: 3

Abstract

The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus Alphavirus), dengue virus (DENV, genus Flavivirus), and zika virus (ZIKV, genus Flavivirus). So far, neither any drug exists against the infection by a single virus, nor against co-infection. The results described in our study demonstrate the inhibitory potential of two flavonoids derived from citrus plants: Hesperetin (HST) against NS2B/NS3(pro) of ZIKV and nsP2(pro) of CHIKV and, Hesperidin (HSD) against nsP2(pro) of CHIKV. The flavonoids are noncompetitive inhibitors and the determined IC50 values are in low mu M range for HST against ZIKV NS2B/NS3(pro) (12.6 +/- 1.3 mu M) and against CHIKV nsP2(pro) (2.5 +/- 0.4 mu M). The IC50 for HSD against CHIKV nsP2(pro) was 7.1 +/- 1.1 mu M. The calculated ligand efficiencies for HST were > 0.3, which reflect its potential to be used as a lead compound. Docking and molecular dynamics simulations display the effect of HST and HSD on the protease 3D models of CHIKV and ZIKV. Conformational changes after ligand binding and their effect on the substrate-binding pocket of the proteases were investigated. Additionally, MTT assays demonstrated a very low cytotoxicity of both the molecules. Based on our results, we assume that HST comprise a chemical structure that serves as a starting point molecule to develop a potent inhibitor to combat CHIKV and ZIKV co-infections by inhibiting the virus proteases. (AU)

• FAPESP's process: 16/12904-0 - Mechanism and Molecular Interactions of Bioactive molecules with NS3 protease from Zika virus.
• Grantee: Monika Aparecida Coronado
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/05614-3 - Identification of bioactive molecules which inhibit both Chikungunya and Mayaro virus activities.
• Grantee: Raphael Josef Eberle
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 18/12659-0 - Mechanisms and Molecular Interactions of Bioactive Molecules with Protein NS3 from Zika Virus - De novo drug design-
• Grantee: Monika Aparecida Coronado
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 18/07572-3 - Exploring the non-structural protease nsP2 from Chikungunya and Mayaro viruses: structures and inhibition.
• Grantee: Raphael Josef Eberle
• Support Opportunities: Scholarships in Brazil - Post-Doctoral