Researchers in the United States have shown that a compound currently used to treat cystinosis exhibits broad antiviral activity against variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19).
The team – from the University of Michigan, Michigan TransTech and BIOQUAL in Rockville, Maryland – found that cysteamine hydrochloride inhibited the infectivity of multiple SARS-CoV-2 lineages in vitro, including the highly contagious B.1.617.2 (delta) variant of concern that has now become the dominant strain worldwide.
Jess Thoene and colleagues also showed that this inhibitory activity manifested during the early stage of viral infection.
Cysteamine is a well-tolerated drug with a good safety profile that has already been approved by the US Food and Drug Administration (FDA) as a topical treatment for a rare genetic disease called cystinosis or cysteine storage disease.
The team suggests that the application of cysteamine as a topical nasal treatment could both mitigate existing SARS-CoV-2 infection and prevent infection in exposed individuals.
A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.
Novel SARS-CoV-2 variants threaten the efficacy of vaccination
Since the COVID-19 outbreak began in late December 2019, unprecedented efforts have been made globally to develop vaccines and antiviral therapies to help combat infection with SARS-CoV-2.
While several vaccines have now been deployed worldwide, their efficacy against newly emerged variants that exhibit increased transmissibility and immune escape has been called into question.
Although these vaccines effectively prevent symptomatic COVID-19, studies have shown that they are less effective at preventing breakthrough infection and the transmission of SARS-CoV-2 from vaccinated individuals to others.
Furthermore, vaccine hesitancy among a substantial proportion of the population has to an extent hampered the successful rollout of mass immunization programs.
Antiviral therapies are needed
Thoene and colleagues say the development of highly effective antiviral therapies that can be used in combination with vaccination is clearly needed to help control the pandemic.
While some antivirals have been shown to inhibit SARS-CoV-2 in vitro, their application in the clinical setting has not yet proved sufficiently effective.
Cysteamine is a simple aliphatic compound used to treat cystinosis – an inborn error of lysosomal cystine transport characterized by failure to thrive, progressive renal failure and end-stage renal disease by the age of 10 years.
Around 800 patients in the United States with nephropathic cystinosis receive cysteamine therapy, which has become the standard of care since its FDA approval was granted in 1994.
Cysteamine has also been investigated as an antiviral agent, with early studies demonstrating its ability to inhibit the infectivity of HIV-1 in vitro.
More recently, the compound has also been shown to inhibit the infectivity of SARS-CoV-2, presumably by blocking the interaction between the receptor-binding domain (RBD) of the viral spike protein and its host cell receptor angiotensin-converting enzyme 2 (ACE-2), say the researchers.
What did the current study involve?
Thoene and colleagues evaluated the antiviral activity of cysteamine hydrochloride (HCl) against wild-type SARS-CoV-2 and the B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and delta variants of concern in a highly permissible Vero cell line.
Cysteamine HCl inhibited the infectivity of both the wild-type virus and the alpha, beta and gamma variants in a dose-dependent manner. Furthermore, a similar dose-dependent inhibition was observed when the delta variant was treated with different concentrations of the compound.
Delta was markedly inhibited by 10 mM cysteamine HCl after 120 minutes of pre-incubation, followed by 60 minutes of Vero cell infection. A similar pattern of delta inhibition was observed when cysteamine HCl was removed following one hour of Vero cell infection, suggesting that inhibition of the virus may have occurred during the first three hours of infection.
The researchers say that cysteamine likely reduces some of the disulfide bonds present in the spike protein of SARS-CoV-2, leading to an altered conformation that inhibits binding of the spike RBD to the ACE2 receptor on target cells.
“Since disulfide residues in the RBD are highly conserved among the emergent variants, it is not surprising that all four variants were sensitive to inhibition by cysteamine HCl,” they write.
Potential application of cysteamine as a nasal treatment
The team says that since it is generally accepted that the nasal epithelium is the initial source of SARS-CoV-2 infection and proliferation, a potential application of cysteamine could be its topical administration to the nasal mucosa of exposed and infected individuals.
In this location, cysteamine could serve as a chemical impediment to both nasal entry and viral replication, suggest the researchers.
“Cysteamine employed as a nasal spray, cream or drops could function as both a preventative and mitigator of infection,” they conclude.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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