Study explores macromolecular viral entry inhibitors as broad-spectrum first-line antivirals with anti-SARS-CoV-2 activities

Various pandemics associated with viral pathogens have occurred in recent decades. The continuing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is one of the worst and has had the largest socioeconomic impact of any of them. It has given a huge boost to vaccine research and testing, but it has also highlighted the various barriers in the field of antiviral medications.

Antiviral drug development has progressed from a nearly desolate sector to over a hundred commercialized drugs in just over 40 years – a remarkable feat of medicinal chemistry.

Background

Polymers are a type of antiviral drug that have an unusually broad spectrum of antiviral activity.

Polymers can engage with the viral exterior, similar to neutralizing antibodies and can block virus contact with the cell. Antiviral polymers can be positively or negatively charged, and they can be made from biological or synthetic materials. The incorporation of hydrophobic groups into the polymer structure provides a unique opportunity to develop virucidal drugs that cause long-term virion destruction.

In a recent study published in Advanced Science, a team of researchers created polystyrene sulfonate (PSS) with significantly different molar masses, constructed these polymers as an exterior around spherical gold nanoparticles of various sizes to improve multivalency effects, measured antiviral effects of the antivirals on numerous viruses in vitro, and investigated the method of interaction of the leads with SARS-CoV-2 and lentiviral particles. In addition, the authors assessed the antivirals' toxicity in mice and assessed antiviral activity in vivo against the respiratory syncytial virus (RSV) and SARS-CoV-2.

FindingsReversible addition-fragmentation chain transfer (RAFT) polymerization was used to produce macromolecular inhibitors based on PSS. The ratio of monomer to RAFT agent was utilized to make polymers with molar masses of 3, 38, and 100 kDa. Recent research suggests that the 3D structure of macromolecular or supramolecular antiviral medicines influences their effectiveness. The size of the nanoparticles has been proven to play an important role in their viral inhibitory efficacy. The authors mounted PSS onto spherical gold nanoparticles ranging in size from 5 to 40 nm to widen the scope of their research.

Coincubation of Au nanoparticles (AuNP) with residual polymer was followed by purification using spin filtering to produce core-shell nanoparticles. UV–vis spectroscopy was used to determine that the nonbound, residual polymer was completely removed from the filtrate solutions. The colloidal stability of the generated core-shell nanoparticles was tested, which is an important feature for biomedical applications. PSS particle functionalization resulted in nanomaterials with high colloidal stability.

PSS decreases the pathogenicity of a broad panel of enveloped viral pathogens, including HIV-1, Zika virus (ZIKV), herpes simplex virus 1 (HSV-1), and RSV, according to previous research by the authors. PSS was also found to inhibit SARS-CoV-2, which is the most important virus in the current pandemic. Even though this inhibition was substantially less potent than that of HIV-1, the potency-related IC50 value was still less than 1 g L-1. With maximally feasible dosages of up to 1.75 mg mL1 on cells, no cytotoxicity was seen at doses required to achieve full inhibition, and only mild impacts on cellular metabolic activity were detected.

The virus's ongoing development and the appearance of several SARS-CoV-2 variants of concern (VOC) is the most pressing concerns during the current pandemic (VOC). Because macromolecular inhibitors of virus-cell entry have a broad spectrum of activity, they could be effective against a variety of variations. To test this, SARS-CoV-2 spike proteins relating to a variety of VOC were generated into rhabdoviral pseudoparticles.

Control inhibitors of viral cell entry and VOC-specific immune evasion included monoclonal antibodies and the REGN-CoV-2 antibody combination. Two antibodies had a narrow range of action against VOC, whereas the combination of antibodies, as well as Imdevimab, were effective against all of the VOCs tested in this study, except Omicron. All VOC were inhibited by the macromolecular inhibitors S3 and BS3. These findings show that antiviral medications based on PSS could be successful against future VOC.

Virions were treated with the polymer or the core-shell formulation at a 0.1 g L1 concentration for 1 minute at 37 °C to see if PSS has antiviral action in vivo in a separate treatment regimen. The combination was then given to the mice intranasally at a quantity of 5 µg per mouse. A second polymer dose was given after 7 hours, and animals were euthanized 48 hours following infection. The viral load was reduced 240-fold in the case of the core-shell particle inhibitor, and 550-fold in the case of PSS taken as a soluble polymer, according to the assessment of viral genome copies. The loss of the viral protein to a level below detectable was confirmed by western blot quantification of the SARS-CoV-2 nucleoprotein, which revealed a considerable loss of the viral protein.

Implications

The polymers described in this study are the first broad-spectrum antiviral compounds to decrease RSV and SARS-CoV-2 proliferation in vivo after intranasal administration, indicating that they could be used as an antiviral nasal spray or inhalation device in the future. When compared to other broad-spectrum antivirals that are taken systemically, this mode of administration may be associated with fewer side effects.

Furthermore, the macromolecular inhibitors' broad-spectrum efficacy against enveloped viral infections makes them ideal for pandemic preparedness to tackle new viruses for which no prophylactic or therapeutic measures exist.

Written by

Colin Lightfoot

Colin graduated from the University of Chester with a B.Sc. in Biomedical Science in 2020. Since completing his undergraduate degree, he worked for NHS England as an Associate Practitioner, responsible for testing inpatients for COVID-19 on admission.