Topical antiseptic acriflavine inhibits SARS-CoV-2 and other betacoronaviruses

Since the emergence and rapid spread of severe acute respiratory syndrome coronavirus (SARS-CoV) in southern China in 2002, scientists have considered coronaviruses a potential threat to humans.

Another member of the coronavirus family, namely Middle East respiratory syndrome coronavirus (MERS-CoV), has shown a high transmission and mortality rate; however, it has not spread across the world.

In late December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was first reported in Wuhan, China, which later caused the ongoing coronavirus disease pandemic in 2019, responsible for the death of more than 5.53 million people worldwide to date. .

Study: Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses. Image Credit: Warah38/Shutterstock

Fund

Several COVID-19 vaccines have received Emergency Use Authorization (EUA) from global regulatory agencies and subsequently vaccination programs have begun in the majority of countries around the world. However, vaccinating the world’s population is not an easy task due to vaccine hesitancy and the shortage of available vaccines.

Additionally, the emergence of SARS-CoV-2 variants posed a threat to vaccine efficacy. Therefore, scientists have highlighted an urgent need for effective antivirals to protect individuals against SARS-CoV-2 infection.

Moreover, since the development of a new drug is a time-consuming process, the reuse of existing drugs with known safety profiles offers an effective option for the treatment of COVID-19.

The researchers proposed that a set of antivirals could be identified and used against SARS-CoV-2 in combination, similar to the combination treatment used for HIV-1.

Scientists have identified the genomic sequences of several structural and non-structural proteins of SARS-CoV-2. Among these, cysteine ​​proteases, namely Mpro (nsp5) and PLpro (nsp3) have been shown to be essential for virus replication.

Even though many studies are available that have focused on the identification of Mpro inhibitors, little evidence is available regarding the identification of PLpro inhibitor. However, previous studies have shown that PLpro is essential for the maturation of viral proteins.

Furthermore, this protease is involved in attenuating the response to type I interferon. These studies indicate that PLpro could be used as a potential therapeutic target.

A new study

A new study published in the journal Cellular Chemical Biology, reported the discovery of acriflavine (ACF), an effective inhibitor of SARS-CoV-2. This drug is a mixture of trypaflavins (3,6-diamino-10-methylacridinium chloride and 3,6-diamino-3-methylacridinium chloride) and proflavine (3,6-diaminoacridine). It has been used for the treatment of many illnesses including urinary tract infections, sleeping sickness and gonorrhea.

ACF has been clinically tested against HIV and has also been given in doses of up to 100 mg per day for several months to patients. Although the chemical structure of ACF indicated possible DNA intercalation and liver toxicity, no adverse effects were observed in the clinical study.

In some countries like Brazil, ACF is available as an over-the-counter medicine for urinary tract infections. In Japan, ACF is used as one of the components of mouthwashes recommended for children. Several studies have shown that ACF can be used alone or in combination with other medications, without significant side effects.

The authors of this study revealed that ACF could inhibit SARS-CoV-2 PLpro and, therefore, it can be used as a potential therapeutic for COVID-19.

Structural characterization of ACF, using X-ray crystallography and NMR, revealed the mode of action of the drug. Scientists have reported that this drug inhibits the active site of the enzyme with an exceptional binding mode. PLpro modulates the ISGylation pathway, which acts as a viral defense mechanism to inhibit normal protein translation. Importantly, PLpro inhibition interferes with viral protein maturation and activates host cellular defense mechanisms to fight COVID-19 infection.

In vitro experiments have also shown that ACF blocks SARS-CoV-2 infection. Additionally, infection was also shown to be suppressed ex vivo in human airway epithelium (HAE) cultures and in vivo experiments using a mouse model. These studies have shown that ACF has excellent pharmacokinetics when administered orally. The authors reported that ACF can inhibit PLpro at low nanomolar range in all models tested. They further revealed that ACF activity exceeds GRL-0617.

Importantly, this study showed the efficacy of ACF against betacoronaviruses, such as MERS-CoV and HCoV-OC43, which have the potential to develop into pandemics. However, ACF has not been shown to be effective against other genera of the Coronaviridae family (alphacoronavirus).

Conclusion

Some of the main advantages of using ACF to treat SARS-CoV-2 infection are its low cost and ease of access. ACF could inhibit SARS-CoV-2 PLpro at low nanomolar IC50 and showed good SI in all models tested.

The authors proposed that ACF could be used as a combination therapy with remdesivir to inhibit viral replication. This treatment could be extremely beneficial for the treatment of elderly people infected with SARS-CoV-2.

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