Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. ahpi 20aioai eius Fjsiae l,19)i yooa ytieppiaeadhsa has and peptidase cysteine lysosomal a three is contains domain 1997) the L al., with The et R). hACE2, (Fujishima and (Adedeji residues) to (L replication acid form attached for two-chain amino cell was (220 host which the L membrane, into Cathepsin to released viral S is the cleaves genome L of viral 2013). human cathepsin the al., and fusion Then SARS-CoV, et SARS-CoV enables 1A). of to cleavage (Fig. endocytosis similar The membrane After activation, endosomal protein indicated 2020). S2. S system al., and SARS-CoV-2 pseudovirus et for S1 protein (Ou coronaviruses, critical S (HIV) some is SARS-CoV-2 of virus B, a The infection immunodeficiency and on not the S1 In exploration L, fusion. between monomer an cathepsin cleavage site. membrane however, each priming that S2’ involved; enables on and process: cleavage is which activating trimeric proteolysis B two-step and S2 is cathepsin RRAR), a protein and by 682-685, activated S acids attachment, is (amino The the S2 protein en- S mediates endocytosis. converting of for which potential angiotensin membrane S1 fusion to cell subunits, (S) host two glycoprotein the Corona contains spike on Syndrome its (hACE2) Respiratory though Acute 2 lactoferrin. Severe binds by zyme by Coronavirus superposed caused heavily is (SARS-CoV-2). (COVID-19) is Virus-2 2019 activity. L disease inhibitory cathepsin coronavirus L of ongoing cathepsin cleft The lactoferrin show in site of useful also active lobe might be the carboxyl-terminal might peptides the that inhibition protein-derived only and selective Food that L This indicated H. cathepsin docking and with Molecular B interacts L. cathepsins cathepsin not of in but targeting (buried L, fine crosslinks cathepsin disulfide inhibit multiple can of Lactoferrin features: contents cathepsin specific low that share or elucidates prevent lack food structure-functionality to core), in of method protein effective found perspective lyso- an proteins/peptides the the considered inhibitory involves from therefore which L Analysis is process, L internalization. proteolysis cathepsin two-step virus of a the Inhibition by L. proceeds cathepsin cells peptidase host somal into SARS-CoV-2 of entry The protein-derived Food Abstract lactoferrin. by inhibition lactoferrin superposed selective of heavily activity. is lobe This inhibitory L carboxyl-terminal L H. cathepsin the cathepsin of and only show cleft that B site also indicated active might cathepsins docking the peptides not that Molecular and L. but L cathepsin L, cathepsin share of with cathepsin targeting interacts food of fine inhibit contents in in low can useful found or Lactoferrin be lack proteins/peptides might core), hydrophobicity. Analysis inhibitory protein surface peptidase internalization. in L virus high lysosomal (buried cathepsin the and crosslinks the prevent that involves disulfide to multiple elucidates which method features: structure-functionality effective process, an specific proteolysis of considered two-step perspective therefore a is the by L from cathepsin proceeds of cells Inhibition host L. into cathepsin SARS-CoV-2 of entry The Abstract 2020 20, July 1 SARS-CoV-2 Madadlou Combat Ashkan to Drugs for Inhibitory Resource Potential L a Cathepsin are Mining Proteins Food Article: Hypothesis aeignUiesti nResearch en Universiteit Wageningen 1 α- ei tutrs(ml eie) n ihsraehydrophobicity. surface high and helices), (small structures helix 1 α- eie oei h ogs eta ei)adteR the and helix) central longest the is (one helices α- ei tutrs(ml helices), (small structures helix Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. rpi/hmtysnihbtrfo oba BII,atpclsrn rtaeihbtr(aaoe al., et (Hatano Bowman-Birk inhibitor with protease commonly homologous is serine core is typical protein arrangement a a This as (BBI-I), common chains. soybean not is side from which hydrophobic inhibitor core, bulky protein trypsin/chymotrypsin the some form with bonds occupied disulfide The protein. the Cys3 between bonds tutr.I scmoe ftodmisAadB aho hc omdb he-taddantiparal- three-stranded a by formed which of each B, and A domains two selec- of consists stem composed cystatin pineapple lel white is in egg It Hen present cystatin. peptide residues) of structure. those a acid from is amino distinct two which remarkably 41 of are 1D) (H, BI-VI (Fig. chain of structures residues)] heavy (K secondary acid kDa; L amino 5.89 cathepsin inhibits 11 [BI-VI; (K tively (L, VI L chain cathepsin inhibitor light inhibits bromelain well and cystatin, as to cystatin-I contrast Corn In 2012). not wedge-shaped al., hydrophobic probably hydrophobic et the that most (Turk with known are cleft associated is × likely active-site residues It cathepsins, their acid 1988). of of amino al., inhibition structure et the 21 for (Abe N-terminal crucial oryzacystatin-I the are of interactions activity and inhibitory 2000) cathepsin al., for essential et (Nagata inhibitory in oryzacystatin-I cathepsin 102) of count several residue 1995), K kDa, constant, al., the (11.4 (inhibition Oryzacystatin-I et L cathepsin (Bonner foods. inhibit × animal activity to and cathepsin known plant is affect in rice Da, identified not of (226 been do carnosine implementation have as chicken) molecules and such and food exploration in meat to peptides in bioactive vision occurring cells. naturally new host some into a Whereas entry confers SARS-CoV-2 cathepsin inhibit characteristic protein/peptide-based can This contain afford that proteins/peptides foods biomolecules food compounds. Certain of However, blockage inhibitory SARS-CoV-2. 2020). as of al., well L et inhibition as (Goudarzi The for Mas, surface receptor opportunities cell patients. how the on further COVID-19 receptor and outlined in I hACE2, type we function of angiotensin over-expression pulmonary the recently were and action proteins, of endocytosis mechanisms and SARS-CoV-2 presumed on peptides implications bioactive have usually fragments, might occurring (small naturally peptides al., protein-derived contains et food (Lankelma food (napsul-Ile-Trp-CHO) 2013). that iCL al., and Given et 2013) which (Adedeji al., epoxyketones, peptidomimetic et dipeptide essentially like (Adedeji are drugs, suppression 2010) inhibitory SARS-CoV has L SSAA09E1 for by cathepsin It used the instance of for are 2010). Many B, al., al., cathepsin endocytosis. et than SARS-CoV-2 et epoxysuccinyl (Lankelma rather and (Fujishima (an L, L E-64 cathepsin CLIK-148 cathepsin of e.g. as inhibit inhibition thiophen-2-ylethylideneamino]thiourea such drugs exclusively the few the derivative) that a shown of aldehyde whereas, been Some (an L, iCL assessment. cathepsin and plethora for including other derivate) a present cathepsins Consequently, in several are implicated made 1997). also inhibit has drugs al., is X/Z 1997) et inhibitory enzyme and (Fujishima The L S, diseases C, cathepsin 2010). periodontal B, al., and of cathepsins et osteoporosis, to (Lankelma as contrast strategies such in anticancer cells, pathologies for cancer target in a H L and cathepsin L SARS-CoV-2 cathepsin of of prevention Full overexpression for The inhibition 2020). inhibited. L and al., cathepsin TMPRSS2 incompletely et of of TMPRSS2, was necessity (Hoffmann inhibition the protease infection fusion for suggesting one membrane serine viral L/B, drugs, cathepsin two cellular priming, for of inhibit protein employment other concurrent the to S cells. the in by used for L accomplished apoptosis the was SARS-CoV-2 was and of inhibition inhibitor by turnover, N-terminus protein the exploited protease to at is serine contributes located proven which L (Cys25) Cathepsin clinically cysteine and 2012). a barrel al., When the et (Turk of top helix central the domain at located (His163) histidine of a is domain 10 10 β- α- –8 -8 he Htn ta. 95.B-Icnan e ytiersde,adfieitaitrcandisulfide intra/inter-chain five and residues, cysteine ten contains BI-VI 1995). al., et (Hatano sheet ei n h v-taddantiparallel five-stranded the and helix α- )adctesnH(K H cathepsin and M) )adctesnH(K H cathepsin and M) eie n v-taddantiparallel five-stranded a and helices β- arl hc scoe ttebto yan by bottom the at closed is which barrel, L -Cys7 H Cys6 , i i 0.2 i 1.0 : 5.7 : × L -Cys39 10 × × } -6 10 10 od rmssfrsprsino ASCV(ddj ta. 2013), al., et (Adedeji SARS-CoV of suppression for premises holds )ada esretn rpi Pla 03.Tepiayand primary The 2003). (Polya, trypsin extent lesser a at and M) -6 –9 H HligradGue,21) yrpoi lse between cluster hydrophobic A 2019). Gruber, and (Hellinger ) Cys8 , )(elne n rbr 2019). Gruber, and (Hellinger M) β- he tutrs(i.1)saiie h ei architecture helix the stabilizes 1C) (Fig. structures sheet β- he,bttescnaysrcueo IV lacks BI-VI of structure secondary the but sheet, L -Cys5 2 < D)ta nuneternnagoesnsystem renin-angiotensin the influence that kDa) 3 α- H i Cys14 , ei Fg B.Teratv iecetcomposes site-cleft reactive The 1B). (Fig. helix 7.3 : × H 10 -Cys21 -10 ) u loctesnB(K B cathepsin also but M), H n Cys18 and , β- H alanyl-L-histidine, -Cys30 H { crosslink [( α- i Z i helix 1.7 : 7.9 : )-1- Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. n h neatosbtentetolbsaemsl yrpoi asdb akn fnnoa surfaces Low nonpolar 2019) of al., packing et 1997). (Wang by al., caused bonds et hydrophobic disulfide mostly 17 (Moore the contains are lobes superposes protein lobes two This C-lobe the the the 2010). on that between that al., indicates interactions shows et the 2017) also (Sreedhara and It al., pH 1F). et The the 1F). (Tiemann on (Fig. (Fig. MDsrv small L depending taken L were cathepsin a using cathepsin SARS- L by with of docking cathepsin obstacle cleft interacts joined and Molecular active-site lactoferrin halves) lactoferrin for of of C-terminal bank. L structures and C-lobe data crystal cathepsin (N-terminal the The protein 1E). of lobes RCSB two polypeptide (Fig. targeting the into single 1997) from fine al., a folded et is enable is (Moore lactoferrin It may (3-turn) Bovine helix This residues. cells. 689 to of jeopardizes 2005). consisting possible al., avoiding 10 while et at internalization, (Sano enzyme CoV-2 cathepsin 10 H the inhibits at strongly cathepsin inhibited place It site and takes milk. active lactoferrin cow’s and L than by His163 milk cathepsin inhabitation Trp189, human L in Gln16, contents Cathepsin of higher L. much chains with at 1997). side inhibitor present al., an of is of et Lactoferrin consists (Fujishima group which Cys25 (carboxyl) L, of carbonyl chain cathepsin the between main of interaction the hole the oxyanion of electrophilic consequence N-terminal a the hydrophilic as of the occur contents may 1988), in L poor al., low also et is and (Abe which hydrophobicity oryzacystatin-I portion to Considerable comparable of that portion cysteine. speculate I lacks account, It into ( 1993). structure al., et (Kumosinski of all 2005). 9peeto.Fo rtisrlaedvrebooial cieppie nete r yrlzdb the L COVID- by cathepsin showing assist hydrolyzed evidences hence are foods, Presently and they in microbes. L once activity from cathepsin peptides and inhibitory inhibit active tract, L to biologically gastrointestinal cathepsin diverse the able in release with be present proteins might peptides enzymes Food proteins and food prevention. protein in 19 present encrypted naturally peptides the Moreover, some in chemistry. to conformation. thiol positioned chain/lobe by addition double bonds, proceeds In a inhibition disulfide L possess several cathepsin BI-VI include place, and earlier L, lactoferrin an cathepsin in both towards mentioned As selectivity core. high protein show which BI-VI, and lactoferrin, between features shared For bonds. single a β- to addition short pH, In one physiological of At molecules. structure hydrophobic secondary structure. by The to protein protected binds the and stabilize and protein that family in lipocalin buried residue of cysteine member a protease cysteine is of lactoglobulin investigated, contents of scarcely significant that has been extent proteins lower have milk a the origin Mammalian lactoferrin, animal Though literature. as of the such inhibitors. foods inhibitors, in L in available cathepsin property are contain inhibitory evidences origin L some could cathepsin animal trypsin with of peptides advantageous. foods required, Therefore, and is resources, essentially 2020). current BI-VI plant al., by not the to et L in but Comparable (Ou cathepsin later L syncytium and discussed of trypsin cathepsin formation is of to enabling selec- which co-inhibition similar protein, inhibition the lactoferrin, S the that with SARS-CoV-2 for noteworthy activate shared important is efficaciously is be It feature might This conformation communication. L. chain double cathepsin crosslinked towards S-S tivity heavily The 1996). atgoui .Asae etr ewe IV and BI-VI between feature shared A B. lactoglobulin β- aen nalsei-yeihbto ehns sblee ocuectesnihbtr Sn tal., et (Sano inhibitory cathepsin cause to believed is mechanism inhibition allosteric-type an casein, β- Beta aenntcag and charge net casein α- β- < ei Rgn ta. 2000). al., et (Ragona helix aenmyntb seta o ahpi niioyatvt.Rte,teCtria hydrophobic C-terminal the Rather, activity. inhibitory cathepsin for essential be not may casein csi 2.8ka sasnl hi oyetd n h othdohbccsi.Essentially casein. hydrophobic most the and polypeptide chain single a is kDa) (23.98 -casein 0)aetesae etrsbetween features shared the are 20%) β- atgoui ,o ahpisKadLhv enosre Oaae l,2009). al., et (Ogawa observed been have L and K cathepsins on A, lactoglobulin β- α- atgoui ossso ieantiparallel nine of consists lactoglobulin β- ei tutr rbbycue h niiin nfc,ihbto fcathepsin of inhibition fact, In inhibition. the causes probably structure helix α- aenand casein ei tutrsaepstoe tteNtria oto ftemolecule the of portion N-terminal the at positioned are structures helix β- atgoui and lactoglobulin Beta α- β- ei otn,salhlcs n yrpoi ufcsaethe are surfaces hydrophobic and helices, small content, helix atgoui.Teihbtr ffc of effect inhibitory The lactoglobulin. lcolblnAhsa diinlngtv hrecmae to compared charge negative additional an has A -lactoglobulin α- ei otn fbvn atfri aisbten7 n 16% and 7% between varies lactoferrin bovine of content helix -5 β- α- 3 .Ntby atfri osntihbtctesnB cathepsin inhibit not does lactoferrin Notably, M. aenand casein helix, β- β- atgoui steeitneo nenldisulfide internal of existence the is B lactoglobulin β- aen ti otyt oeta ohlactoferrin both that note to worthy is It casein. atgoui xssa urmlclrdimer. supramolecular a as exists lactoglobulin β- -7 atgoui a nenldsld linkages disulfide internal 2 has lactoglobulin ,wie ytei etd hc targets which peptide synthetic a while, M, β- atgoui .Tkn hydrophobicity Taking B. lactoglobulin β- hes he eia un n only and turns helical three sheets, β- atgoui ,as at also B, lactoglobulin α- Beta- helix Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. e,HS,adLe ..(00.CtesnBihbtr etdsdrvdfrom derived peptides inhibitory B Cathepsin (2000). al. K.J. et Lee, De, 807–809. Sci. A.P.N.A. and Porto, Life H.S., der, treatment? Van Lee, cancer A.H. in Spek, target J., L, Koetsveld, Cathepsin T., Barwari, (2010). D.M., Voorend, Bovine J.M., of Lankelma, Modeling Molecular Three-Dimensional Energy-Minimized (1993). H.M. An Farrell, Caseins: and E.M., Inhibitor. Brown, Protease T.F., Proven Clinically Kumosinski, a by Blocked Is and TMPRSS2 and Cell ACE2 Kr on Depends S., Entry Cell Schroeder, CoV-2 Today H., Kleine-Weber, Discov. Drug M., plants. Hoffmann, from inhibitors from protease inhibitor Peptide-based trypsin/chymotrypsin (2019). 24 C.W. Birk Gruber, - and R., Bowman Hellinger, with similarity inhibitor bromelain Structural of Biochemistry structure Solution stem: soybean. (1996). pineapple K. Takahashi, from and M., VI Tanokura, M., Stem. Kojima, Pineapple Sequence-Specific K.I., from Hatano, Structure, VI Inhibitor Primary Bromelain (1995). of Biochem. K. Solution J. Takahashi, in and Eur. Structure M., Secondary Tanokura, and Assignments Hypertens. M., 1H-NMR J. Kojima, antihypertensive -i, foes? protein-derived K. of Food Hatano, friends crystal (2020). pandemic: V. The COVID-19 Fogliano, the and (1997). in A., T. Lett. peptides Madadlou, Sugawara, FEBS F., Garavand, and E-64. M., Y., with Goudarzi, Yamamoto, complexed Y., L Fujisawa, cathepsin Alcohol human T., feeding. of Nomura, nonlysoso- ethanol structure and Y., to Lysosomal Imai, response (1995). A., in V.R. Fujishima, brain Preedy, the and of L.C., In- activities Heap, Novel protease J.S., Marway, mal (2013). M.E., S.G. Swann, Mechanisms. Distinct A.B., Sarafianos, Three Bonner, and by Act S.R., That Weiss, Entry K., Coronavirus Super- Virol. Syndrome Singh, Cystatin J. Respiratory C., the Acute Severe of Jonsson, of Member W., hibitors Residues a Severson, Acid , A.O., Amino 21 Oryzacystatin Adedeji, NH2-terminal of The Chem. Activity (1988). Papain-inhibitory Biol. K. J. the Suzuki, and family. for S., Essential Arai, Not H., Kondo, Are Y., Emori, K., Abe, interest References of discovery. conflict drug not the declares accelerate egg author and can hen The separation sequences food conditions, that peptide peptide Besides, hydrolysis known known active The the established. biologically is literature. bonds. are of of the it peptides property disulfide Hundreds in these example, nine known of inexpensive. For are by procedures and proteins purification crosslinking (GRAS) food proteins. of safe from white derived as degree sequences egg recognized This high also generally a characterized. are but extensively has proteins proteins, are protein proteins milk (or riboflavin-binding food for exclusively advantageous.white many highly true that of be especially peptides characteristics can is of biofunctional cathepsins other and Isolation the structural L. than The L cathepsin cathepsin inhibit inhibit can preferentially) from more peptides derived much protein-derived peptides inhibitory food B whether cathepsin Two of digestion scarce. are peptides protein-derived β- food by inhibitory aenwr dnie napnrai ieto aen(e n e,20) swl sppie rmthe from peptides as well as 2000), Lee, and (Lee casein of digest pancreatic a in identified were casein 1877–1889. : 181 271-280.e8. : 87 8017–8028. : β- atgoui ya noetds ol nii ahpi .I ean ob explored be to remains It K. cathepsin inhibit could endopeptidase an by B lactoglobulin 232 335–343. : 263 35 5379–5384. : 7655–7659. : β- aenSrcue .DiySci. Dairy J. Structure. Casein gr . ere,T,Eihe,S,e l 22) SARS- (2020). al. et S., Erichsen, T., Herrler, N., uger, ¨ 4 nsilico In 86 225–233. : 76 xmnto ftectesnLinhibitory L cathepsin the of examination 407 38 931–945. : 1614–1616. : 47–50. : 12 505–509. : β- aen Peptides casein. 21 : Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. n ieto.Ci.Rv odSi Nutr. Sci. denaturation Food function, Structure, Rev. From Lactoferrin: Crit. (2019). Proteomics cathepsins: B. digestion. Adhikari, Proteins Cysteine and and - E., (2012). Blanch, Y.P., Acta al. Timilsena, Biophys. B., et Wang, Biochim. B., Turk, frontiers. T., new Sun, to M., regulation 68–88. Renko, and O., function Vasiljeva, structure, V., Stoka, Methods V., Nat. Turk, web. Dairy the sharing Int. on and viewing simulations lactoferrin. MDsrv: dynamics bovine (2017). molecular and A.S. compar- Rose, caprine A Guix`a-Gonz´alez, and of P.W., J.K.S., (2010). conformation Hildebrand, Tiemann, and R., al. stability et P., thermal Kaul, the T., on Int. Langsrud, pH J. Res. of D., protease Food Krowarsch, effects Cysteine V., of food. (2005). Prakash, ison a R., al. as Flengsrud, et importance A., Q.T., its Sreedhara, Le, and E., preparations Murata, milk K., various Yamauchi, in N., Takakura, inhibitors R., Miyauchi, Bovine of E., (2000). Sci. glycoprotein al. Sano, Protein et spike De, acid. of K. palmitic 567–641. Kruif, Characterization with P., pp Puyol, P´erez, studies D.M., L., Plants. (2020). Interaction Zetta, from F., Inhibitors al. Fogolari, L., Protease et Commun. Ragona, Non-Protein L., Nat. and Ren, SARS-CoV. Protein with D., (2003). cross-reactivity Mi, G.M. immune Polya, P., its Li, and entry X., virus Lei, on Y., SARS-CoV-2 Liu, Collagenoly- X., of Ou, Inhibition (2009). N. (Tokyo). KATUNUMA, Biochemistry Vitaminol. and by japonica. K., Cathepsins L. structure ISHIDOH, sativa tic solution M., Oryza Three-dimensional TAKAHASHI, rice, (2000). N., OGAWA, the M. Tanokura, of and inhibitor S., proteinase Arai, cysteine 14753–14760. K., a Abe, oryzacystatin-I, struc- N., of Three-dimensional Kudo, (1997). K., E.N. 2.8 Baker, Nagata, at and lactoferrin M., bovine Haridas, diferric C.R., of Groom, ture B.F., Anderson, S.A., Moore, 20 487–494. : β- atgoui nMl n t upesv ffc nBn eopin .Nt.Sci. Nutr. J. Resorption. Bone on Effect Suppressive Its and Milk in Lactoglobulin 55 264–270. : eouin .Ml Biol. Mol. J. resolution. A ˚ 59 580–596. : 9 5 :. 14 1123–1124. : 274 222–236. : 38 427–433. : β- lactoglobulin: 11 1620. : 1824 39 : : Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. 6 Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. E D C B 7 Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. 8 Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. 10 Posted on Authorea 20 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159526748.87772484 — This a preprint and has not been peer reviewed. Data may be preliminary. niio IadlcoernseiclyihbtctesnL(oohrcathepsins); lactoferrin. other bovine (no by L suprposed cathepsin L inhibit cathpesin specifically human lactoferrin Blue: and of L; VI cathepsin structures inhibitor native drawing and of Ribbon VI form 2012); two-chain inhibitor al., the 2013); of et al., (Turk fold et the (His163) Adedeji ribbon: from Green (adopted L. membrane α- cathepsin endosomal the of with structure membrane drawing viral the of fusion 1. Fig. eie;Red: helices; A fe noyoi fSR-o,ctesnLcevsSR- oS n 2 loigsubsequent allowing S2, and S1 to SARS-S cleaves L cathepsin SARS-CoV, of endocytosis After ) β- hes aladsik h iecan fteratv-iecsen Cs5 n histidine and (Cys25) cysteine reactive-site the of chains side the stick: and Ball sheets; E iercbvn atfri,wihso ahpi niioyatvt.Bromelain activity. inhibitory L cathepsin show which lactoferrin, bovine diferric ) 11 C yttnadoryzacystatin, and cystatin ) F tutrldaig of drawings Structural ) D bromelain ) B) Ribbon