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Hypericin Suppresses SARS-CoV-2 Replication and Synergizes with Antivirals via Dual Targeting of RdRp and 3CLpro

by Martins, Jéssica Santa Cruz Carvalho , Souza, Thiago Moreno Lopes e , Fintelman-Rodrigues, Natalia , Matos, Aline da Rocha , Sardar, Saiqa , Sousa, Thiagos das Chagas , Souza, Helena da Silva , Siqueira, Marilda Mendonça , Silva-Trujillo, Lina , Fernandes, Jorge Hernandes

in 3CLpro / Antiviral activity / Antiviral agents / Antiviral drugs / COVID-19 / COVID-19 vaccines / Cytotoxicity / Dengue viruses / Development and progression / Enzymes / Health aspects / Hypericin / Hypoxemia / Immunomodulators / Infections / Influenza / Influenza A / Intensive care / Monoclonal antibodies / Multiple organ dysfunction syndrome / Pathogens / Pathophysiology / RdRp / RNA polymerase / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Thrombosis / variants / Vector-borne diseases / Viral diseases / Viral infections / Viruses

2025

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Hypericin Suppresses SARS-CoV-2 Replication and Synergizes with Antivirals via Dual Targeting of RdRp and 3CLpro

2025

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Hypericin Suppresses SARS-CoV-2 Replication and Synergizes with Antivirals via Dual Targeting of RdRp and 3CLpro

2025

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Journal Article

Hypericin Suppresses SARS-CoV-2 Replication and Synergizes with Antivirals via Dual Targeting of RdRp and 3CLpro

Martins, Jéssica Santa Cruz Carvalho,

Souza, Thiago Moreno Lopes e,

Fintelman-Rodrigues, Natalia,

Matos, Aline da Rocha,

Sardar, Saiqa,

Sousa, Thiagos das Chagas,

Souza, Helena da Silva,

Siqueira, Marilda Mendonça,

Silva-Trujillo, Lina,

Fernandes, Jorge Hernandes

2025

Overview

The continuous emergence of SARS-CoV-2 variants underscores the need for novel antiviral candidates. Hypericin (HY), a compound derived from Hypericum perforatum, exhibited potent in vitro activity against SARS-CoV-2 in Vero E6 cells, with low cytotoxicity (CC50 > 200 nM). HY showed no significant activity against Influenza A (H1N1) or dengue virus serotype 2, supporting its selective action. Antiviral effects were most evident when HY was administered post-infection, in a concentration-dependent manner, while cellular pretreatment or viral pre-incubation produced limited effects. Notably, HY also displayed virucidal activity, significantly reducing viral titers at 4 °C, 22 °C, and 37 °C. Combination treatments with remdesivir or nirmatrelvir enhanced antiviral efficacy by 50–70% relative to monotherapy, depending on compound concentration. Molecular simulations revealed stable interactions with conserved residues in RdRp and 3CLpro, suggesting a low risk of resistance. Together, these findings highlight the potential of HY as a selective antiviral and virucidal agent against SARS-CoV-2, particularly in combination regimens.

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