Identification of Hypericin as a Candidate Repurposed Therapeutic Agent for COVID-19 and Its Potential Anti-SARS-CoV-2 Activity

Abstract

The COVID-19 pandemic has had an unprecedented impact on the global economy and public health. Its etiologic agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible, pathogenic and has a rapid global spread. Currently, the increase in the number of new confirmed cases has been slowed down due to the increase of vaccination in some regions of the world. Still, the rise of new variants has influenced the detection of additional waves of rising cases that some countries have experienced. Since the virus replication cycle is composed of many distinct stages, some viral proteins related to them, as the main-protease (Mpro) and RNA dependent RNA polymerase (RdRp), constitute individual potential antiviral targets. In this study, we challenged the mentioned enzymes against compounds pre-approved by health regulatory agencies in a virtual screening and later in Molecular Mechanics/Poisson–Bolzmann Surface Area (MM/PBSA) analysis. Our results showed that, among the identified potential drugs with anti-SARS-CoV-2 properties, Hypericin, an important component of the Hypericum perforatum that presents antiviral and antitumoral properties, binds with high affinity to viral Mpro and RdRp. Furthermore, we evaluated the activity of Hypericin anti-SARS-CoV-2 replication in an in vitro model of Vero-E6 infected cells. Therefore, we show that Hypericin inhibited viral replication in a dose dependent manner. Moreover, the cytotoxicity of the compound, in cultured cells, was evaluated, but no significant activity was found. Thus, the results observed in this study indicate that Hypericin is an excellent candidate for repurposing for the treatment of COVID-19, with possible inhibition of two important phases of virus maturation.

Hypericum perforatum and Its Ingredients Hypericin and Pseudohypericin Demonstrate an Antiviral Activity against SARS-CoV-2

“…Furthermore, pre-treatments of cells do not block virus infectivity, arguing against a Hypericum perforatum -mediated blockade of the SARS-CoV-2 receptor ACE2. On the other hand, potential modes of antiviral actions of Hypericum perforatum against SARS-CoV-2 were introduced, since hypericin and pseudohypericin were anticipated, by molecular docking, to form a stable complex with the main (3CL) protease or the RNA polymerase of the SARS-CoV-2 [ 62 , 63 ] or had a high affinity toward SARS-CoV-2 basic proteins [ 64 ] but with only little clarification about biological evidence so far. However, it was found that some plant polyphenols could inhibit the 3CL protease using certain experimental settings [ 65 ].…”

Phytochemical Drug Discovery for COVID-19 Using High-resolution Computational Docking and Machine Learning Assisted Binder Prediction

“…For example, agathisflavone demonstrates a high binding affinity to the helicase (7NIO), main protease (7AR5), and NSP15 (6VWW), and hypericin demonstrates strong binding to the main protease (6Y2E), NSP9 (6WXD), and the spike protein (6VXX). Other molecular docking studies have shown that our main protease leads agathisflavone, 94 amentoflavone, 95 ginkgetin, 96 procyanidin b2, 97 bilobetin, 96 and hypericin 98 are good binders against the main protease. Moreover, we found that other molecular docking studies mention some of the same interacting residues that we observed for our main protease leads hypericin, 99 ginkgetin, 100 bilobetin, 100 and procyanidin b2.…”

HTP SurflexDock: a web tool for Structure-Based Virtual Screening analysis based on the Ensemble Docking protocol

“…Moreover, Hypericin obtained promising results with a ΔΔG = -22.704 ± 4.008 Kcal/mol, and thus its antiviral activity was evaluated in Vero E6 cells incubated with the new coronavirus. The results indicated that Hypericin caused a significant reduction of viral RNA in the supernatant at concentrations between 10 and 100 µM and exhibited a low cytotoxic activity at these concentrations [Matos et al 2022].…”