Morphogenetic (Mucin Expression) as Well as Potential Anti-Corona Viral Activity of the Marine Secondary Metabolite Polyphosphate on A549 Cells

Abstract

The mucus layer of the nasopharynx and bronchial epithelium has a barrier function against inhaled pathogens such as the coronavirus SARS-CoV-2. We recently found that inorganic polyphosphate (polyP), a physiological, metabolic energy (ATP)-providing polymer released from blood platelets, blocks the binding of the receptor binding domain (RBD) to the cellular ACE2 receptor in vitro. PolyP is a marine natural product and is abundantly present in marine bacteria. Now, we have approached the in vivo situation by studying the effect of polyP on the human alveolar basal epithelial A549 cells in a mucus-like mucin environment. These cells express mucins as well as the ectoenzymes alkaline phosphatase (ALP) and adenylate kinase (ADK), which are involved in the extracellular production of ATP from polyP. Mucin, integrated into a collagen-based hydrogel, stimulated cell growth and attachment. The addition of polyP to the hydrogel significantly increased cell attachment and also the expression of the membrane-tethered mucin MUC1 and the secreted mucin MUC5AC. The increased synthesis of MUC1 was also confirmed by immunostaining. This morphogenetic effect of polyP was associated with a rise in extracellular ATP level. We conclude that the nontoxic and non-immunogenic polymer polyP could possibly also exert a protective effect against SARS-CoV-2-cell attachment; first, by stimulating the innate antiviral response by strengthening the mucin barrier with its antimicrobial proteins, and second, by inhibiting virus attachment to the cells, as deduced from the reduction in the strength of binding between the viral RBD and the cellular ACE2 receptor.

Recent Advances on Nanomaterials to COVID‐19 Management: A Systematic Review on Antiviral/Virucidal Agents and Mechanisms of SARS‐CoV‐2 Inhibition/Inactivation

“…[45] We collected data from several nanostructures' types studied against the coronavirus cited above as nanotubes, nanorods, nanoparticles, nanostars, nanowires, nanocrystals, nanosheets, nanogels, nanospheres, nanocapsules, nanoclusters, and nanostructured lipid carriers (NLCs). Of these, were identified the following nanotechnology-based approaches: bioconjugated carboxyl quantum dots (QDs); [74] silver nanomaterials; [58,60,69,80,96,97] synthetic virus-like particles (sVLPs); [77] gold nanoparticles; [59,77] biopolymeric/biodegradable polymeric nanoparticles and hydrogels (e.g., chitosan, collagen, poly(ethylene glycol) (PEG), poly lactic-co-glycolic acid (PLGA), and poly(hydroxyethyl) methacrylate); [61,62,63,79,[85][86][87]91,93] carbon quantum dots (CQDs) [71] and cationic carbon dots based on curcumin (CCM-CDs); [68] glutathione(GSH)-capped silver-sulfide nanoclusters (GSHcapped Ag 2 S NCs); [64] gold nanorod-based heptad repeat 1 (HR1) peptide; [72] antigen and adjuvant-loaded hollow polymeric nanoparticles; [73] bovine serum albumin (BSA)-coated tellurium nanoparticles (Te/BSA NPs) with a unique triangular star shape (Te/BSA nanostars); [65] GSH-modified zinc-sulfide nanoparticles (ZnS NPs); [66] glycyrrhizic-acid-based carbon dots (Gly-CDs); [67] multi-walled carbon nanotubes (MWCNTs) with target functions; [83] metal-decorated single-wall carbon nanotubes (SWCNTs); [100] NLCs; [88] graphene oxide; [60,82,92] iron oxide nanoparticles (IONPs), [75] functionalized graphene sheets;…”

“…From Table 6, we note that most of all nanoparticles studied are spherical and presented an impressive average size varying from 11.4 to 1.5 nm in the last 3 years reported atte mpts. [63,64,[66][67][68]91,93] Figure 6 shows a schematic representation of some strategies reviewed on active phytochemicals (a broad-spectrum "host-targeted" antiviral)/nanoparticles systems as promising candidates against coronaviruses as virus adsorbents, antiviral agents. and immunomodulatory drugs.…”

“…[63] PolyP, a non-toxic and non-immunogenic inorganic polymer derived from marine bacteria, was added into a mucin/collagenbased hydrogel to simulate the mucus of the nasopharynx and bronchial epithelium on human alveolar basal epithelial A549 cells. [91] This strategy was suggested to stimulate an innate antiviral response by improved mucin barrier (high in antimicrobial proteins) and as a potential antiviral agent by exerting protection against SARS-CoV-2-cell attachment. [91] Griffithsin is a small lectin derived from red algae (Griffithsia spp.)…”

Caged Dexamethasone/Quercetin Nanoparticles, Formed of the Morphogenetic Active Inorganic Polyphosphate, are Strong Inducers of MUC5AC

“…Interestingly, the phosphoryl transfer reaction catalyzed by the bacterial phosphite-NAD + oxidoreductase seems to involve the formation of a metaphosphate intermediate [93], as proposed for the formation of ADP from polyP by the ALP [17]. Besides the morphogenetic activities of the three components, the release of ATP during ALP degradation of the caged NP in the concert with the mucin expression [94] also has a potential organizing effect on the mucin layer on the surface of the endothelial cells of the airways system; Figure 10. While ATP certainly has a determining effect on goblet cells that produce the mucins, it might also have a structure-giving and form-formatting function during the association processes of the mucin molecules after the explosive exocytic release of the mucin granules [95], as shown in Figure 10.…”

New Hopes for Drugs against COVID-19 Come from the Sea

“…Marine Drugs has published six articles on marine molecules with potential against coronavirus, including three review articles [ 4 , 5 , 6 ] and three research papers [ 7 , 8 , 9 ]. In two of these [ 7 , 8 ], the authors suggest that another marine natural polymer, the inorganic polyP, abundantly present in marine bacteria, is worthy of further investigation for its activity in strengthening the mucin barrier and inhibiting viral attachment to the cells.…”