Virucidal and antiviral activity of astodrimer sodium against SARS-CoV-2 in vitro

Paull, Jeremy Ra; Heery, Graham; Bobardt, Michael; Castellarnau, Alex; Luscombe, Carolyn A.; Fairley, Jacinth K.; Gallay, Philippe

doi:10.1016/j.antiviral.2021.105089

Cited by 25 publications

(20 citation statements)

References 41 publications

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“…[58] More recently, SPL7013 demonstrated antiviral activity against SARS-CoV-2 in vitro at concentrations found in their Viraleze antiviral nasal spray. [59] In addition to heparan sulfate, sialic acid, which is found on the terminal branches of N-and O-glycans, is another well-established binding motif, [56a] with the α5-N-acetylneuramic acid (Neu5AC) form recognized as the preferred attachment point for influenza A and B viruses. [60] Sialic acid has also been identified as a binding target of coronavirus spike proteins.…”

Section: Synthetic Antiviral Polymersmentioning

confidence: 99%

Bioactive Synthetic Polymers

et al. 2021

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Progress in these arenas has been driven by the discovery of inert, biocompatible polymers to provide the desired function without eliciting undesirable responses from the host environment. While concerns regarding the fate of these materials have led to an ongoing hunt for bioresorbable materials, it is important to note that synthetic polymers have been reported to elicit a biological response on their own. [2j,5] While the biological response is often toxic in nature and therefore undesirable for many applications, it poses a question: can the intrinsic bioactivity of synthetic polymers be harnessed for therapeutic interventions? This idea of intrinsic bioactivity is distinct from the long history of work pertaining to the use of synthetic polymers within biomedical settings. Polymers have indeed been extensively explored and continue to be investigated as (nano)carriers facilitating the delivery of bioactive payloads; in the majority of cases, the (nano)carrier bereft of its cargo is presented to provide little to no effect, demonstrating its role as an ideal delivery vehicle. [6] Polymers with intrinsic bioactivity diverge from this well-known concept by inducing biological change (i.e., bioactivity) by themselves in the absence of any conjugated or encapsulated species. [7] Interestingly, this previously posed question generated significant interest prior to the advent of drug-delivery approaches. [8] Among these early studies, a synthetic polymer, designated DIVEMA, garnered significant attention for its presentation of an outstanding breadth of bioactivity. [9] DIVEMA is a copolymer of divinyl ether (DVE) and maleic anhydride (MA) in a 1:2 ratio, with its proposed cyclopolymerization mechanism affording an in-chain pyran which consequently caused it to be more prominently known as Pyran copolymer. A hydrolyzed and neutralized version received the designation NSC 46015 and was approved for experimental clinical evaluation due to its antitumor activity against several cancers, including Adenocarcinoma 755, Lewis lung carcinoma, and Dunning ascites leukemia. [10] Moreover, its ability to induce interferon expression led to its evaluation against several viruses and reports of prophylactic action in murine models. DIVEMA has also demon strated antimicrobial activity against both Grampositive and Gram-negative bacteria and fungi. Despite this wide-ranging bioactivity, DIVEMA also presented a number of toxic side effects, the summation of which was not favorable for clinical use. Such side effects were common to many of the investigated synthetic polymers of the time and their failure in clinical trials is reflected in an absence of such therapeutic interventions as approved medicines.Synthetic polymers are omnipresent in society as textiles and packaging materials, in construction and medicine, among many other important applications. Alternatively, natural polymers play a crucial role in sustaining life and allowing organisms to adapt to their environments by performing key biological functions such as m...

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Section: Synthetic Antiviral Polymersmentioning

confidence: 99%

Bioactive Synthetic Polymers

et al. 2021

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“…The single exposure of the virus to astodrimer sodium 1% nasal spray formulation for 60 min in the virucidal study (Group 3.2) did not result in the absence of the virus detected in nasal secretions but did result in a lack of viraemia compared to the PBS control (Group 3.1). In vitro virucidal studies by our group demonstrated a reduction in viral titre of up to 99.99% when 1% astodrimer sodium was used to block SARS-CoV-2 (USA-WA1/2020) infection [ 2 ]. Whilst the current virucidal in vivo study demonstrates partial protection from exposure to 3 × 10 2 PFU SARS-CoV-2 (USA-WA1/2020), the results suggest at least one virus escaped and established a very low-grade infection.…”

Section: Resultsmentioning

confidence: 99%

“…The quantitation of the infectious virus in the tissue homogenates was performed by plaque assay, as described in Paull et al, 2021 [ 2 ], with Vero E6 cells as the detecting cell line.…”

Section: Methodsmentioning

confidence: 99%

“…Astodrimer sodium is a large (3–4 nm, ~16.5 kDa), negatively charged, highly-branched dendrimer that has significant antiviral and virucidal activity against different isolates of SARS-CoV-2 in vitro [ 2 ]. Its mechanism of action is primarily to act as a barrier to block the binding of the highly positively charged SARS-CoV-2 spike protein to its receptor-complex, which includes the angiotensin converting enzyme 2 (ACE2) receptor.…”

Section: Introductionmentioning

confidence: 99%

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Protective Effects of Astodrimer Sodium 1% Nasal Spray Formulation against SARS-CoV-2 Nasal Challenge in K18-hACE2 Mice

Paull

Luscombe

Castellarnau

et al. 2021

Viruses

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Strategies to combat COVID-19 require multiple ways to protect vulnerable people from infection. SARS-CoV-2 is an airborne pathogen and the nasal cavity is a primary target of infection. The K18-hACE2 mouse model was used to investigate the anti-SARS-CoV-2 efficacy of astodrimer sodium formulated in a mucoadhesive nasal spray. Animals received astodrimer sodium 1% nasal spray or PBS intranasally, or intranasally and intratracheally, for 7 days, and they were infected intranasally with SARS-CoV-2 after the first product administration on Day 0. Another group was infected intranasally with SARS-CoV-2 that had been pre-incubated with astodrimer sodium 1% nasal spray or PBS for 60 min before the neutralisation of test product activity. Astodrimer sodium 1% significantly reduced the viral genome copies (>99.9%) and the infectious virus (~95%) in the lung and trachea vs. PBS. The pre-incubation of SARS-CoV-2 with astodrimer sodium 1% resulted in a significant reduction in the viral genome copies (>99.9%) and the infectious virus (>99%) in the lung and trachea, and the infectious virus was not detected in the brain or liver. Astodrimer sodium 1% resulted in a significant reduction of viral genome copies in nasal secretions vs. PBS on Day 7 post-infection. A reduction in the viral shedding from the nasal cavity may result in lower virus transmission rates. Viraemia was low or undetectable in animals treated with astodrimer sodium 1% or infected with treated virus, correlating with the lack of detectable viral replication in the liver. Similarly, low virus replication in the nasal cavity after treatment with astodrimer sodium 1% potentially protected the brain from infection. Astodrimer sodium 1% significantly reduced the pro-inflammatory cytokines IL-6, IL-1α, IL-1β, TNFα and TGFβ and the chemokine MCP-1 in the serum, lung and trachea vs. PBS. Astodrimer sodium 1% nasal spray blocked or reduced SARS-CoV-2 replication and its sequelae in K18-hACE2 mice. These data indicate a potential role for the product in preventing SARS-CoV-2 infection or for reducing the severity of COVID-19.

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“…This molecule has now shown activity against newly discovered variants of concern including the Alpha or UK (B.1.1.7) and the more recent Delta SARS-CoV-2 variant [159]. A recent article by Paull et al found that astodrimer sodium (SPL7013) can inhibit the replication of SARS-CoV-2 in vivo, and such irreversibly blocked interaction leads SARS-CoV-2 to no longer infect cells [160]. Starpharma also announced the release of a nasal spray [161] under the tradename VIRALEZE™ as a promising weapon against COVID-19 that will aid in filling the gap during challenging global vaccine rollouts [162].…”

Section: Peptide Multimers As Antimicrobial and Antiviral Agentsmentioning

confidence: 99%

Peptide Multimerization as Leads for Therapeutic Development

Sheard

O'Brien-Simpson

et al. 2021

Biologics

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Multimerization of peptide structures has been a logical evolution in their development as potential therapeutic molecules. The multivalent properties of these assemblies have attracted much attention from researchers in the past and the development of more complex branching dendrimeric structures, with a wide array of biocompatible building blocks is revealing previously unseen properties and activities. These branching multimer and dendrimer structures can induce greater effect on cellular targets than monomeric forms and act as potent antimicrobials, potential vaccine alternatives and promising candidates in biomedical imaging and drug delivery applications. This review aims to outline the chemical synthetic innovations for the development of these highly complex structures and highlight the extensive capabilities of these molecules to rival those of natural biomolecules.

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Virucidal and antiviral activity of astodrimer sodium against SARS-CoV-2 in vitro

Cited by 25 publications

References 41 publications

Bioactive Synthetic Polymers

Bioactive Synthetic Polymers

Protective Effects of Astodrimer Sodium 1% Nasal Spray Formulation against SARS-CoV-2 Nasal Challenge in K18-hACE2 Mice

Peptide Multimerization as Leads for Therapeutic Development

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