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Elucidation of the mechanism of anti-herpes action of two novel semisynthetic cardenolide derivatives

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Abstract

Human herpesviruses are among the most prevalent pathogens worldwide and have become an important public health issue. Recurrent infections and the emergence of resistant viral strains reinforce the need of searching new drugs to treat herpes virus infections. Cardiac glycosides are used clinically to treat cardiovascular disturbances, such as congestive heart failure and atrial arrhythmias. In recent years, they have sparked new interest in their potential anti-herpes action. It has been previously reported by our research group that two new semisynthetic cardenolides, namely C10 (3β-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin) and C11 (3β-(hydroxyacetyl)amino-3-deoxydigitoxigenin), exhibited potential anti-HSV-1 and anti-HSV-2 with selectivity index values > 1,000, comparable with those of acyclovir. This work reports the mechanism investigation of anti-herpes action of these derivatives. The results demonstrated that C10 and C11 interfere with the intermediate and final steps of HSV replication, but not with the early stages, since they completely abolished the expression of the UL42 (β) and gD (γ) proteins and partially reduced that of ICP27 (α). Additionally, they were not virucidal and had no prophylactic effects. Both compounds inhibited HSV replication at nanomolar concentrations, but cardenolide C10 was more active than C11 and can be considered as an anti-herpes drug candidate including against acyclovir-resistant HSV-1 strains.

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Abbreviations

ACV:

acyclovir

CC50 :

50% cytotoxic concentration

CMC:

carboxymethylcellulose

DEX-S:

dextran sulfate

FBS:

fetal bovine serum

HIV:

human immunodeficiency virus

HSV-1:

herpes simplex virus type 1

HSV-2:

herpes simplex virus type 2

HPV:

human papillomavirus

IC50 :

concentration that inhibited 50% of viral replication

MEM:

Eagle’s minimum essential medium

MOI:

multiplicity of infection

PBS:

phosphate-buffered saline

PFU:

plaque-forming units

SI:

selectivity index

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Acknowledgements

The authors thank the Brazilian funding agencies CAPES (MEC), Fapemig (APQ-00538-17, RMP) and CNPq (MCTI) for research fellowships, as well as CNPq for financial support (grant numbers 305878/2016-6, CMOS, and 490057/2011-0, FCB). They are also grateful to BAYLAT (JM and RMP for mobility support) and Marie Curie Foundation/European Community (FP7 IRSES, grant 295251, WK).

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  1. Laboratório de Virologia Aplicada, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, 88040-970, Brazil

    Laurita Boff, Naira Fernanda Zanchett Schneider & Cláudia Maria Oliveira Simões

  2. Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, 31270-901, Brazil

    Flaviano Melo Ottoni, Gabriela Silva Ramos, Fernão Castro Braga, Ricardo José Alves & Rodrigo Maia de Pádua

  3. Pharmaceutical Biology, Department of Biology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

    Jennifer Munkert & Wolfgang Kreis

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  1. Laurita Boff
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Boff, L., Schneider, N.F.Z., Munkert, J. et al. Elucidation of the mechanism of anti-herpes action of two novel semisynthetic cardenolide derivatives. Arch Virol 165, 1385–1396 (2020). https://doi.org/10.1007/s00705-020-04562-1

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