From Springer Nature via Jisc Publications RouterHistory: received 2020-03-25, accepted 2020-04-10, registration 2020-04-11, pub-electronic 2020-05-12, online 2020-05-12, pub-print 2020-08Publication status: Publishe

Jones, Samuel T.

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INVITED VIEWPOINTHow materials can beat a virusSamuel T. Jones1,2,*1Department of Materials, University of Manchester, Oxford Road, Manchester M13 9PL, UK2The Henry Royce Institute, Alan Turing Building, Oxford Road, Manchester M13 9PL, UKReceived: 25 March 2020Accepted: 10 April 2020Published online:12 May 2020 The Author(s) 2020At the end of 2019 reports started to surface of anovel viral infection that has become known as SARS-CoV-2 (causing the infection COVID-19) and wasclassified as a pandemic by the World Health Orga-nization (WHO) in March 2020. Countries around theworld have utilised a range of measures to face thispandemic and although each country has their ownunique approach, it has typically included periods ofself-isolation or quarantine to help limit both thespread of the virus and the burden on health caresystems. During these periods of self-isolation, manyhave been asking themselves what they can do tohelp. There have been some uplifting reports ofeveryone pulling together to do their part, whetherthat is breweries, distilleries or perfume manufac-turers making hand sanitiser, [4] or collaborativeteams of engineers and scientists working together toproduce and redesign ventilators [2].But what could a materials chemist do to help?Viruses are often thought of as being a problem to beresolved by biologists and biochemists, yet in reality,there are many crossovers with chemistry andmaterials, ready to be exploited [11].Viruses are intracellular parasites with a verysimple structure. They lack their own metabolismand require a host to replicate, so are (debatably) notliving [8]. Instead viruses can be thought of as self-assembled nanostructures, typically comprised ofproteins, genetic material, and often a lipid mem-brane. Prof. Palli Thordarson (Department of Chem-istry, The University of New South Wales (UNSW))recently highlighted this in a Twitter thread [13],showing why it is so important to use soap whenwashing your hands to destroy viruses like SARS-CoV-2.The key characteristic behind why soap is soeffective is linked directly to the fact that viruses areself-assembled structures. Their lipid membranes arecomprised of fatty acids with hydrophobic interac-tions between chains, leading to a stable outermembrane. When you introduce soap into the mix-ture these hydrophobic interactions are disruptedAddress correspondence to E-mail: samuel.jones-4@manchester.ac.ukhttps://doi.org/10.1007/s10853-020-04678-4J Mater Sci (2020) 55:9148–9151Invited iewpointand the lipid membrane is ‘dissolved’, destroying ordeactivating the virus. Materials capable of destroy-ing a virus in such a way are termed virucidal (Fig. 1)and there are many examples: bleach, alcohol and, asalready mentioned, soap. This is a simple approach todestroying a virus and it is widely used in manyareas from virology labs, (Virkon—used to steriliseand decontaminate surface) through to hospitals (al-cohol hand gel). Yet, it is not possible to use soap (orother virucides) as an internal treatment because theexact same process that destroys the virus would alsodestroy our own cells.On the topic of treatment options for viruses, thereare two main approaches to antivirals, intracellularand extracellular, both of which can benefit greatlyfrom input from materials chemists.Intracellular antivirals are almost exclusivelysmall-molecule drugs that are designed to inhibit theintracellular replication of viruses, for example someof the promising candidates for treating SARS-CoV-2:Remdesivir (Fig. 2), which was originally developedfor Ebola [14], and Kaletra (ritonavir and lopinavircombination), originally designed for HIV [1].As with the majority of these intracellular drugs,they are designed to be effective against a specificvirus and although they may be effective againstother viruses, there are no guarantees. To ensuresuccess, each drug would need to redesigned using,for example, in silico studies or a process of trial anderror; however, this would mean a re-design forevery viral outbreak. An intracellular approach doesnot readily lend itself towards a broad-spectrumdrug, because each virus utilises a different replica-tion pathway to multiply.A broad-spectrum antiviral, similar to broad-spectrum antibiotics, would rapidly treat newlyemerging viral outbreaks. Extracellular antivirals,unlike intracellular antivirals, become important hereas they have potential to be the most broad spectrum.There are many types of extracellular antivirals, butthe most common are ‘entry inhibitors’—another areawhere materials chemists can get their hands dirty.Entry inhibitors are, in general, materials that bindto the virus surface and block the interactions withthe host cells, thereby stopping the virus from beingable to infect. As different viruses can use the same(or similar) initial attachment receptors on the surfaceof cells [5]; these entry inhibitors can be designed tomimic such receptors. In doing so, these materialsshow broad-spectrum activity with other viruses thatuse the same initial attachment receptors.In principal, these sound like our best approach;however, the interaction between material and viruscan be reversible (termed virustatic) and so with asimple change in dilution, pH or temperature theinfective virion would be released. There have beenmany examples of broad-spectrum virustatic mate-rials including polymers [9, 12], dendrimers [10], andnanoparticles [3] and all show very low levels oftoxicity. Yet, when it comes to their use as a treat-ment, these virustatic materials fall short because inthe in vivo environment dilution occurs readily,leading to release of the intact virion [12].What if we could take these non-toxic, broad-spectrum entry inhibitors, modify them and changetheir mode of action from virustatic to virucidal? Thischange would lead to a material that was able todestroy a wide range of viruses on contact (i.e. broadspectrum) while remaining non-toxic. This mightsound too good to be true, but my colleagues and Irecently discovered materials capable of doing justthat [6, 7].By modifying a sugar macrocycle, calledcyclodextrin, with alkyl sulfonates, we were able toshow broad-spectrum virucidal effects against viru-ses that use cell-surface heperan sulfates as theirVirucidalMaterial+VirusFigure 1 Cartoon depicting the affect a virucidal material has ona virus.OPOOHNOOOHO OHNNNNH2NFigure 2 Chemical structure of Remdesivir, a potential antiviralcandidates for treatment of COVID-19.J Mater Sci (2020) 55:9148–9151 9149initial attachment receptors (Fig. 3). These include,but are not limited to, human immunodeficiencyvirus (HIV) (EC50 ¼ 3:35 lM), herpes simplex virus 1(HSV-1) (EC50 ¼ 15:3 lM), herpes simplex virus 2(HSV-2) (EC50 ¼ 8:61 lM), respiratory syncytial virusA (RSV-a) (EC50 ¼ 2:99 lM), Dengue virus(EC50 ¼ 4:63 lM), Zika virus (EC50 ¼ 0:2 lM) andhepatitis C (EC50 ¼ 2:04 lM). As well as being broadspectrum, these modified cyclodextrins were viruci-dal and showed very low toxicity in vitro. Weobserved that the linker length between thecyclodextrin backbone and the sulfonate group wascritical for achieving this virucidal mechanism, withshorter alkyl linkers leading to poorer EC50’s andloss of the virucidal mechanism.Through the use of molecular dynamic simula-tions, we show that upon binding of the modifiedcyclodextrins to the attachment receptor of the HSV2virus, the protein trimer is altered only in the pres-ence of the virucidal cyclodextrin variant.Initial tests of these antivirals against SARS-CoV-2has shown promising efficacy, but further tests areneeded to confirm this finding. The key now is to tryand develop these types of materials, not only forclinical use in the fight against SARS-CoV-2 (if nee-ded), but also ultimately so that they are ready for thenext inevitable viral outbreak.This represents only one example of a material-based approach that can be used in the fight againstviral infections. There are many other avenueswaiting to be explored (such as antiviral face masksor antiviral surfaces) that offer materials chemistsfurther opportiunities to apply their expertise to thevirus problem.Compliance with ethical standardsConflict of interest The authors declare that theyhave no conflict of interest.Open Access This article is licensed under aCreative Commons Attribution 4.0 InternationalLicense, which permits use, sharing, adaptation,distribution and reproduction in any medium orformat, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link tothe Creative Commons licence, and indicate if chan-ges were made. The images or other third partymaterial in this article are included in the article’sCreative Commons licence, unless indicated other-wise in a credit line to the material. If material is notincluded in the article’s Creative Commons licenceand your intended use is not permitted by statutoryregulation or exceeds the permitted use, you willneed to obtain permission directly from the copyrightholder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.References[1] Kaletra (2020) https://www.ema.europa.eu/en/medicines/human/EPAR/kaletra. Accessed 10 Apr 2020[2] Ventilatorchallengeuk consortium—home page (2020) https://www.ventilatorchallengeuk.com. Accessed 10 Apr 2020[3] Baram-Pinto D, Shukla S, Perkas N, Gedanken A, Sarid R(2009) Inhibition of herpes simplex virus type 1 infection bysilver nanoparticles capped with mercaptoethane sulfonate.Bioconj Chem 20(8):1497–1502. https://doi.org/10.1021/bc900215b[4] Brunner J (2020) Complete list of distilleries (includinganheuser-busch) making hand sanitizers instead of spirits. https://parade.com/1011922/jerylbrunner/distilleries-making-hand-sanitizer/. Accessed 10 Apr 2020[5] Cagno V, Tseligka ED, Jones ST, Tapparel C (2019) Heparansulfate proteoglycans and viral attachment: true receptors oradaptation bias? Viruses 11(7):596. https://doi.org/10.3390/v11070596[6] Cagno V, Andreozzi P, D’Alicarnasso M, Jacob Silva P,Mueller M, Galloux M, Le Goffic R, Jones ST, Vallino M,Hodek J, Weber J, Sen S, Janeček ER, Bekdemir A, SanavioFigure 3 Cryo-transmission electron microscopy images of theHerpes Simplex Virus 2 (HSV-2) before (left) and after (right)interacting with the virucidal cyclodextrin variant. Scalebar = 100 nm.9150 J Mater Sci (2020) 55:9148–9151B, Martinelli C, Donalisio M, RameixWelti MA, Eleouet JF,Han Y, Kaiser L, Vukovic L, Tapparel C, Král P, Krol S,Lembo D, Stellacci F (2017) Broad-spectrum non-toxicantiviral nanoparticles with a virucidal inhibition mecha-nism. Nat Mater 17:195–203. https://doi.org/10.1038/nmat5053[7] Jones ST, Cagno V, Janeček M, Ortiz D, Gasilova N, Piret J,Gasbarri M, Constant DA, Han Y, Vuković L, Král P, KaiserL, Huang S, Constant S, Kirkegaard K, Boivin G, Stellacci F,Tapparel C (2020) Modified cyclodextrins as broad-spectrumantivirals. 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How materials can beat a virus

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How materials can beat a virus

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