Antiviral biomaterials

Abstract

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alerts to the urgency to develop efficient antiviral agents to fight the coronavirus disease 2019 (COVID-19) pandemic as well as other future viral infections under epidemic or pandemic scenarios. The existing small-molecule antiviral medications in use display severe side effects, limiting their long-term administration. Based on recent advances and advantages in materials science, various biomaterials targeting the different steps of viral infection have suggested promising efficiencies. For example, the antiviral biomaterials can physically adsorb viruses, inhibit viral entry by binding to viruses, generate irreversible viral deformation, interfere with viral nucleic acid replication, or block the viral release from infected cells. This review intends to motivate further research and developments in this critical, yet overall under-investigated, field by presenting up-to-date information on antiviral biomaterials and highlighting emerging opportunities and bottlenecks. Viral infections remain one of the leading causes of mortality worldwide, responsible for millions of deaths every year. The application of antiviral drugs, along with symptomatic treatment, is the primary modality of clinical antiviral therapy. Nevertheless, the severe side effects of antiviral drugs, such as gastrointestinal, hepatic, renal, and/or hematopoietic damages, can affect compliance and may even interrupt treatment. Moreover, drug resistance due to frequent viral mutations and single antiviral mechanisms often leads to therapeutic failure. The introduction of biomaterials into antiviral therapy provides distinct advantages and unique mechanisms. Antiviral biomaterials work in various ways, such as physical adsorption of viruses, binding to viruses as entry inhibitors, induction of irreversible viral deformation, interference with viral nucleic acid replication, and blockage of viral release from infected cells, among others. This review offers an overview of state-of-the-art advances in antiviral biomaterials featuring different mechanisms and discusses their challenges and opportunities in clinical translations. Viral infections remain one of the leading causes of mortality worldwide, responsible for millions of deaths every year. The application of antiviral drugs, along with symptomatic treatment, is the primary modality of clinical antiviral therapy. Nevertheless, the severe side effects of antiviral drugs, such as gastrointestinal, hepatic, renal, and/or hematopoietic damages, can affect compliance and may even interrupt treatment. Moreover, drug resistance due to frequent viral mutations and single antiviral mechanisms often leads to therapeutic failure. The introduction of biomaterials into antiviral therapy provides distinct advantages and unique mechanisms. Antiviral biomaterials work in various ways, such as physical adsorption of viruses, binding to viruses as entry inhibitors, induction of irreversible viral deformation, interference with viral nucleic acid replication, and blockage of viral release from infected cells, among others. This review offers an overview of state-of-the-art advances in antiviral biomaterials featuring different mechanisms and discusses their challenges and opportunities in clinical translations. Viral infections cause various diseases, leading to millions of deaths globally every year and imposing a tremendous economic burden on our society.1Lozano R. Naghavi M. Foreman K. Lim S. Shibuya K. 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Role of metal and metal oxide nanoparticles as diagnostic and therapeutic tools for highly prevalent viral infections.Nanomedicine. 2017; 13: 219-230Google Scholar Their interactions with mammalian cells, bacteria, and viruses can be programmed based on varying functional requirements. Over the past few decades, numerous biomaterials have been developed to fight cancer,20Nam J. Son S. Park K.S. Zou W. Shea L.D. Moon J.J. Cancer nanomedicine for combination cancer immunotherapy.Nat. Rev. Mater. 2019; 4: 398-414Google Scholar create vaccines,21Al-Halifa S. Gauthier L. Arpin D. Bourgault S. Archambault D. Nanoparticle-based vaccines against respiratory viruses.Front. Immunol. 2019; 10: 22Google Scholar control bacterial infections,22Zaidi S. Misba L. Khan A.U. Nano-therapeutics: A revolution in infection control in post antibiotic era.Nanomedicine. 2017; 13: 2281-2301Google Scholar and treat viral infections.23Rai M. Deshmukh S.D. Ingle A.P. Gupta I.R. Galdiero M. Galdiero S. 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Antimicrobial nanomaterials and coatings: Current mechanisms and future perspectives to control the spread of viruses including SARS-CoV-2.ACS Nano. 2020; 14: 12341-12369Google Scholar Antiviral biomaterials have been designed to combat different types of viruses and have achieved promising results in pre-clinical models. VivaGel® (SPL7013 Gel), developed by Starpharma, is on the market for treatment of HIV and herpes simplex virus (HSV).28Price C.F. Tyssen D. Sonza S. Davie A. Evans S. Lewis G.R. et al.SPL7013 Gel (VivaGel®) retains potent HIV-1 and HSV-2 inhibitory activity following vaginal administration in humans.PLoS One. 2011; 6e24095Google Scholar Similarly, a phase II trial of the topical antiviral nanoemulsion (NB-001) has demonstrated potent activity against HSV-I.29Kircik L. Jones T.M. Jarratt M. Flack M.R. Ijzerman M. Ciotti S. Sutcliffe J. Boivin G. Stanberry L.R. Baker J.R. Treatment with a novel topical nanoemulsion (NB-001) speeds time to healing of recurrent cold sores.J. Drugs Dermatol. 2012; 11: 970-977Google Scholar In contrast to existing antiviral drugs, the antiviral mechanisms of biomaterials are generally novel and, thus, would likely prevent the buildup of drug resistance. The basic structure of a complete virus particle (virion) consists of nucleic acid (DNA or RNA) and a protein layer (capsid) to protect the nucleic acid.30Fuenmayor J. Gòdia F. Cervera L. Production of virus-like particles for vaccines.Nat. Biotechnol. 2017; 39: 174-180Google Scholar For enveloped viruses, the envelopes originate from portions of the host cell membranes decorated with viral glycoproteins. Glycoproteins on the surface of the envelope, such as hemagglutinin and neuraminidase, serve to identify and bind to receptor sites on the membranes of host cells, leading to activation of the viral infectious cycle.31Vahey M.D. Fletcher D.A. Low-fidelity assembly of influenza A virus promotes escape from host cells.Cell. 2019; 176: 281-294.e19Google Scholar The viral infection cycle involves attachment onto the host cell membrane, penetration into the cell, uncoating the capsid to release nucleic acid, biosynthesis of viral nucleic acid and proteins, virus assembly, and virion release from the infected cells (Figure 1). The antiviral actioning mechanisms of biomaterials can be based upon the interference of viral entry (attachment and penetration), the prevention of viral nucleic acid replication (biosynthesis of viral nucleic acid and proteins), or the inhibition of viral release from infected cells (virion release) (Figure 1). The capture of viruses by biomaterials via virus–biomaterial interactions and the destruction of viral structures through forces are both unique antiviral mechanisms of biomaterials, where the surface characteristics of the biomaterials play a vital role in the mechanisms of their antiviral actions.32de Souza E Silva J.M. Hanchuk T.D.M. Santos M.I. Kobarg J. Bajgelman M.C. Cardoso M.B. Viral inhibition mechanism mediated by surface-modified silica nanoparticles.ACS Appl. Mater. Inter. 2016; 8: 16564-16572Google Scholar For example, glycopolymers with a complex-type sialyl N-linked oligosaccharide can strongly bind with surface proteins on the viruses.33Tanaka T. Ishitani H. Miura Y. Oishi K. Takahashi T. Suzuki T. Shoda S.I. Kimura Y. Protecting-group-free synthesis of glycopolymers bearing sialyloligosaccharide and their high binding with the influenza virus.ACS Macro Lett. 2014; 3: 1074-1078Google Scholar Alternatively, sulfonate groups on the biomaterials can bind to positively charged amine groups of lysine residues with Gibbs free energy at the surface of human papillomavirus (HPV) capsid L1 proteins, and the binding energy generates forces to destroy viral structures.34Jones S.T. Cagno V. Janeček M. Ortiz D. Gasilova N. Piret J. et al.Modified cyclodextrins as broad-spectrum antivirals.Sci. Adv. 2020; 6eaax9318Google Scholar, 35Rafiei S. Rezatofighi S.E. Ardakani M.R. Madadgar O. In vitro anti-foot-and-mouth disease virus activity of magnesium oxide nanoparticles.IET Nanobiotechnol. 2015; 9: 247-251Google Scholar, 36Qin T. Ma R. Yin Y. Miao X. Chen S. Fan K. Xi J. Liu Q. Gu Y. Yin Y. Catalytic inactivation of influenza virus by iron oxide nanozyme.Theranostics. 2019; 9: 6920-6935Google Scholar These biomaterial designs can be unconventional yet effective options for the adsorption of viruses for antiviral purpose. Moreover, drawbacks in the physicochemical and pharmacokinetic properties of existing antiviral drugs, such as low solubility, poor permeability, short circulation half-life, insufficient targeting ability, and low bioavailability, have restricted their efficacy. To resolve these problems, various biomaterials, such as nanoparticles and hydrogels, have been developed as carriers that contain antiviral drugs against different viral infections.16Lembo D. Cavalli R. Nanoparticulate delivery systems for antiviral drugs.Antivir. Chem. Chemother. 2010; 21: 53-70Google Scholar,37Durai R.D. Drug delivery approaches of an antiviral drug: A comprehensive review.Asian J. Pharm. 2015; 9: 1-12Google Scholar, 38Singh L. Indermun S. Govender M. Kumar P. du Toit L.C. Choonara Y.E. et al.Drug delivery strategies for antivirals against hepatitis B virus.Viruses. 2018; 10267Google Scholar, 39Mhlwatika Z. Aderibigbe B.A. Application of dendrimers for the treatment of infectious diseases.Molecules. 2018; 232205Google Scholar Interestingly, several nanoparticle formulations have displayed greater inhibition efficiencies of viral nucleic acid replication than traditional antiviral medicines.40Ghaffari H. Tavakoli A. Moradi A. Tabarraei A. Bokharaei-Salim F. Zahmatkeshan M. et al.Inhibition of H1N1 influenza virus infection by zinc oxide nanoparticles: Another emerging application of nanomedicine.J. Biomed. Sci. 2019; 2670Google Scholar In addition, several biomaterials have been proven to block the release of viruses from infected cells.41Torres N.I. Noll K.S. Xu S. Li J. Huang Q. Sinko P.J. Wachsman M.B. Chikindas M.L. Safety, formulation and in vitro antiviral activity of the antimicrobial peptide subtilosin against herpes simplex virus type 1.Probiotics Antimicrob. Proteins. 2013; 5: 26-35Google Scholar, 42Noordeen F. Scougall C.A. Grosse A. Qiao Q. Ajilian B.B. Reaiche-Miller G. et al.Therapeutic antiviral effect of the nucleic acid polymer REP 2055 against persistent duck hepatitis B virus infection.PLoS One. 2015; 10e0140909Google Scholar, 43Lin Z. Li Y. Gong G. Xia Y. Wang C. Chen Y. et al.Restriction of H1N1 influenza virus infection by selenium nanoparticles loaded with ribavirin via resisting caspase-3 apoptotic pathway.Int. J. Nanomedicine. 2018; 13: 5787-5797Google Scholar This review primarily discusses the basic principles and progressions of functional biomaterials that either display antiviral activities themselves or serve as antiviral agent delivery systems toward representative virus types. Numerous previously published review articles focusing on treating a particular viral infection by biomaterials provide preliminary knowledge for this comprehensive review.44Bianculli R.H. Mase J.D. Schulz M.D. Antiviral polymers: Past approaches and future possibilities.Macromolecules. 2020; 53: 9158-9186Google Scholar, 45Smith A.A.A. Kryger M.B.L. Wohl B.M. Ruiz-Sanchis P. Zuwala K. Tolstrup M. Zelikin A.N. Macromolecular (pro)drugs in antiviral research.Polym. Chem. 2014; 5: 6407-6425Google Scholar, 46Tu Z. Guday G. Adeli M. Haag R. Multivalent interactions between 2D nanomaterials and biointerfaces.Adv. Mater. 2018; 30: 1706709Google Scholar We first introduce biomaterials that can capture viruses and interfere with the entry of viruses. Subsequently, we summarize biomaterials used to destroy the viral structures, inhibit viral replication, and block viral release from infected cells. Furthermore, we highlight biomaterial-mediated multi-antiviral effects, after which we discuss the advantages of biomaterials with these novel antiviral mechanisms and their transformative potential. Finally, we present emerging opportunities and bottlenecks of antiviral biomaterials. Existing antiviral therapeutics lose efficacy over time due to frequent virus mutations, raising the urgent need to develop alternative treatment approaches (Table 1). To meet the growing demand for new antiviral methods, a unique approach was designed to use high-affinity biomaterials for capturing viruses.47Spaltenstein A. Whitesides G.M. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza virus.J. Am. Chem. Soc. 1991; 113: 686-687Google Scholar Since the outer capsids of viruses have abundant surface proteins, biomaterials with high-affinity polymers that can adhere to these surface proteins could be the basis of ideal and creative antiviral therapeutics. Some biomaterials can capture viruses, rendering them unable to infect cells, and subsequently generating an immunogenic reaction via antigen-presenting cells for clearance. These high-affinity biomaterials could be prepared by molecular imprinting technology or other methods.48Sankarakumar N. Tong Y.W. Preventing viral infections with polymeric virus catchers: A novel nanotechnological approach to anti-viral therapy.J. Mater. Chem. B. 2013; 1: 2031-2037Google Scholar Hemagglutinin proteins on a virus can bind with glycoligands, such as sialyl lactose, on the surface of host cells to facilitate viral penetration.31Vahey M.D. Fletcher D.A. Low-fidelity assembly of influenza A virus promotes escape from host cells.Cell. 2019; 176: 281-294.e19Google Scholar Thus, hemagglutinin is an attractive target for antiviral biomaterial design. This section focuses on biomaterials that specifically bind with targeted viruses.Table 1Biomaterials for virus capture and relevant antiviral mechanismsType of biomaterialType of virusAntiviral mechanismRef.Sialyl lactose-chitosan fiberInfluenza virusSialyl lactose had a high affinity to hemagglutinin and captured viruses effectively49Li X. Wu P. Gao G.F. Cheng S. Carbohydrate-functionalized chitosan fiber for influenza virus capture.Biomacromolecules. 2011; 12: 3962-3969Google ScholarPolyacrylamides with pendant α-sialic acidInfluenza virusα-Sialic acid interacted with hemagglutinin and captured viruses47Spaltenstein A. Whitesides G.M. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza virus.J. Am. Chem. Soc. 1991; 113: 686-687Google Scholar,50Lees W.J. Spaltenstein A. Kingery-Wood J.E. Whitesides G.M. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: Multivalency and steric stabilization of particulate biological systems.J. Med. Chem. 1994; 37: 3419-3433Google ScholarGlycopolymer bearing sialyl oligosaccharideInfluenza virusSialyl N-linked oligosaccharide bound with influenza virus51Mammen M. Dahmann G. Whitesides G.M. Effective inhibitors of hemagglutination by influenza virus synthesized from polymers having active ester groups. Insight into mechanism of inhibition.J. Med. Chem. 1995; 38: 4179-4190Google Scholarα-Glucuronic acid-linked cyclodextrin nanoparticleInfluenza virusSialic acid had a high affinity to hemagglutinin and bound with influenza virus strongly52Ogata M. Umemura S. Sugiyama N. Kuwano N. Koizumi A. Sawada T. Yanase M. Takaha T. Kadokawa J.I. Usui T. Synthesis of multivalent sialyllactosamine-carrying glyco-nanoparticles with high affinity to the human influenza virus hemagglutinin.Carbohydr. Polym. 2016; 153: 96-104Google ScholarPLGA nanospongeSARS-CoV-2PLGA nanoparticles coated by membrane of human lung epithelial type II cells or human macrophages could neutralize viral infections53Zhang Q. Honko A. Zhou J. Gong H. Downs S.N. Vasquez J.H. Fang R.H. Gao W. Griffiths A. Zhang L. Cellular nanosponges inhibit SARS-CoV-2 infectivity.Nano Lett. 2020; 20: 5570-5574Google ScholarPLGA nanodecoyHIVPLGA nanoparticles coated by T cell membrane could capture HIV54Wei X. Zhang G. Ran D. Krishnan N. Fang R.H. Gao W. Spector S.A. Zhang L. T-cell-mimicking nanoparticles can neutralize HIV infectivity.Adv. Mater. 2018; 30: 1802233Google ScholarGelatin nanodecoyZIKVGelatin nanoparticles camouflaged by the host cell membrane could capture ZIKV55Rao L. Wang W. Meng Q.F. Tian M. Cai B. Wang Y. Li A. Zan M. Xiao F. Bu L.L. A biomimetic nanodecoy traps Zika virus to prevent viral infection and fetal microcephaly development.Nano Lett. 2018; 19: 2215-2222Google ScholarvMIP, viMIPPhageMIPs exhibited a high affinity to viruses and could capture viruses effectively48Sankarakumar N. Tong Y.W. Preventing viral infections with polymeric virus catchers: A novel nanotechnological approach to anti-viral therapy.J. Mater. Chem. B. 2013; 1: 2031-2037Google Scholar,56Li N. Liu Y. Liu F. Luo M. Wan Y. Huang Z. Liao Q. Mei F. Wang Z. Jin A. Bio-inspired virus imprinted polymer for prevention of viral infections.Acta Biomater. 2017; 51: 175-183Google ScholarHIV, human immunodeficiency virus; PLGA, poly(L-lactide-co-glycolide); SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; viMIP, virus-immobilized molecularly imprinted polymer nanoparticle; vMIP, virus surface-imprinted nanoparticle; ZIKV, Zika virus. Open table in a new tab HIV, human immunodeficiency virus; PLGA, poly(L-lactide-co-glycolide); SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; viMIP, virus-immobilized molecularly imprinted polymer nanoparticle; vMIP, virus surface-imprinted nanoparticle; ZIKV, Zika virus. Li et al.49Li X. Wu P. Gao G.F. Cheng S. Carbohydrate-functionalized chitosan fiber for influenza virus capture.Biomacromolecules. 2011; 12: 3962-3969Google Scholar prepared two sialyl lactose-incorporated chitosan-based biomaterials, either as water-soluble polymer or functional fiber, to capture the influenza virus. These two biomaterials were synthesized by grafting lactoside, bearing an aldehyde-functionalized aglycon ligand onto the amino groups of chitosan or chitosan fiber, followed by enzymatic hydrolysis with sialyltransferase (Figures 2A–2C). The water-soluble sialyl lactose-chitosan demonstrated a high affinity to hemagglutinin and was shown to capture influenza viruse effectively. Furthermore, the sialyl lactose-functionalized chitosan fiber mat was porous, implying that the modification could not only occur on the surface but also internally, where the functionalized fiber was able to adsorb the viruse in an aqueous medium (Figure 2D). The chitosan backbone containing a functional ligand that allowed multiple interactions, such as hydrogen bond, hydrophobic interaction, and van der Waals force, was an appealing approach to implement into the development of antiviral biomaterials for the prevention and control of influenza viral infection. Furthermore, polyacrylamide with pendant α-sialic acid groups was developed to inhibit the agglutination of erythrocytes caused by the influenza virus.47Spaltenstein A. Whitesides G.M. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza virus.J. Am. Chem. Soc. 1991; 113: 686-687Google Scholar,50Lees W.J. Spaltenstein A. Kingery-Wood J.E. Whitesides G.M. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: Multivalency and steric stabilization of particulate biological systems.J. Med. Chem. 1994; 37: 3419-3433Google Scholar A glycopolymer bearing a complex-type sialyl N-linked oligosaccharide was also reported to strongly bind to the influenza virus, which was ascribed to the glycocluster effect and the biantennary structure of N-linked oligosaccharide.33Tanaka T. Ishitani H. Miura Y. Oishi K. Takahashi T. Suzuki T. Shoda S.I. Kimura Y. Protecting-group-free synthesis of glycopolymers bearing sialyloligosaccharide and their high binding with the influenza virus.ACS Macro Lett. 2014; 3: 1074-1078Google Scholar,51Mammen M. Dahmann G. Whitesides G.M. Effective inhibitors of hemagglutination by influenza virus synthesized from polymers having active ester groups. Insight into mechanism of inhibition.J. Med. Chem. 1995; 38: 4179-4190Google Scholar Multivalent sialoglyco-conjugated nanoparticle using highly branched α-glucuronic acid-linked cyclodextrin as a backbone was found to have a high affinity to the human influenza virus hemagglutinin. When there were 30 terminal sialic acid residues on the backbone, the biomaterial would firmly bind with enveloped viruse.52Ogata M. Umemura S. Sugiyama N. Kuwano N. Koizumi A. Sawada T. Yanase M. Takaha T. Kadokawa J.I. Usui T. Synthesis of multivalent sialyllactosamine-carrying glyco-nanoparticles with high affinity to the human influenza virus hemagglutinin.Carbohydr. Polym. 2016; 153: 96-104Google Scholar The distance and multiplicity of binding sites affected ligand-virus formation, which played a crucial role in antiviral efficacy. These results indicated that biomaterials decorated with multivalent sialic acid groups could be a promising strategy for developin