Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range.This work has been supported by the Spanish MINECO (Project
SAF2012-39760-C02-01, cofinanced by the FEDER program; Plan Nacional
de Cooperación Público-Privada; and Subprograma INNPACTO
IPT-2012-0213-060000, cofinanced by the FEDER program) and the Comunidad
de Madrid (BIPEDD2-CM-S2010/BMD-2457). This work was
also funded by EU FP7 (FP7/2007-2013) Project EUVIRNA under Grant408 Agreement 264286 by EU FP7 SILVER (Contract HEALTH-F3-2010-
260644), a grant from the Belgian Interuniversity Attraction Poles (IAP)
Phase VII–P7/45 (BELVIR), and the EU FP7 Industry-Academia Partnerships
and Pathways Project AIROPICO. The Spanish MEC/MINECO is
also acknowledged for a grant to E.R.-B. L.S. was funded by China Scholarship
Council (CSC) Grant 201403250056.
We also acknowledge Charlotte Vanderheydt for help with the processing
of the antiviral data.Peer Reviewe

Camarasa Rius, María José

Delang, Leen

Donckers, K.

García Doyagüez, Elisa

Leyssen, Pieter

Martínez-Gualda, B.

Neyts, Johan

Quesada, ﻿Ernesto

Rivero-Buceta, Eva

San-Félix, Ana

Sun, L.

PubMed

Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range.status: publishe

Sun, Liang

Martínez-Gualda, Belén

Doyagüez, Elisa G

Donckers, Kim

Quesada, Ernesto

Camarasa, María-José

Lirias

Antimicrobial Agents and Chemotherapy

Optimization of a class of tryptophan dendrimers that inhibit HIV replication leads to a selective, specific, and low-nanomolar inhibitor of clinical isolates of enterovirus A71

ABSTRACT
          Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range.</jats:p

Eva Rivero-Buceta

Liang Sun

Belén Martínez-Gualda

Elisa G. Doyagüez

Kim Donckers

Ernesto Quesada

María-José Camarasa

Leen Delang

Ana San-Félix

Johan Neyts

Pieter Leyssen

Crossref

Optimization of a Class of Tryptophan Dendrimers That Inhibit HIV Replication Leads to a Selective, Specific, and Low-Nanomolar Inhibitor of Clinical Isolates of Enterovirus A71

Martínez-Gualda, Belén

Doyagüez, Elisa G.

Digital.CSIC

Optimization of a Class of Tryptophan Dendrimers That Inhibit HIVReplication Leads to a Selective, Specific, and Low-NanomolarInhibitor of Clinical Isolates of Enterovirus A71Eva Rivero-Buceta,a,b Liang Sun,c Belén Martínez-Gualda,a Elisa G. Doyagüez,a,d Kim Donckers,c Ernesto Quesada,aMaría-José Camarasa,a Leen Delang,c Ana San-Félix,a Johan Neyts,c Pieter LeyssencInstituto de Química Médica (CSIC), Madrid, Spaina; Instituto de Tecnología Química (UPV-CSIC), Valencia, Spainb; KU Leuven–University of Leuven, Department ofMicrobiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgiumc; Centro de Química Orgánica ManuelLora Tamayo, Madrid, SpaindTryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unex-pectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Den-drimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series,is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomo-lar/high-picomolar range.Enterovirus A71 (EV71) is a small virus (30 nm) with a single-stranded positive-sense RNA genome of7.4 kb that belongsto the genus Enterovirus of the family Picornaviridae (1, 2). EV71 isthe etiologic agent of hand, foot, and mouth disease (HFMD), amild syndrome that most frequently affects children younger than6 years and that is characterized by the development of fever withskin vesicles on the palms and feet, as well as ulcers on the oralmucosa (3). Unlike other HFMD-associated enteroviruses, EV71can also cause severe neurological problems, such as aseptic men-ingitis and brain stem encephalitis, which can lead to cardiopul-monary failure and death (4–6). After having suffered from suchneurological complications, survivors often have permanent neu-rological sequelae, such as delayed neurodevelopment, reducedcognitive function, and polio-like paralysis (7). Similar to otherhuman enteroviruses, such as poliovirus, transmission of EV71occurs through the fecal-oral route (8).In recent years, large outbreaks of EV71 have been reportedthroughout the world, and they have been particularly severe inthe Pacific region of Asia, with a high number of fatal cases amongchildren (9–11). So far, there is no drug on the market to treat orprevent this infection. An inactivated EV71 vaccine was recentlyapproved in China (12), but it may induce only limited cross-neutralization between EV71 genogroups, which does not make itsuitable for widespread use.Recently, we reported on the anti-HIV activity of a dendrimerfamily containing different central scaffolds and multiple (9 to 18)peripheral tryptophan (Trp) groups (Fig. 1, compounds 1 to 11)that are linked to the dendrimer branches through an aminogroup. These compounds were shown to inhibit an early step inthe replication cycle of HIV by interacting with glycoproteinsgp120 and gp41 of the HIV envelope (13). Further exploration invirus-cell-based assays for broad-spectrum antiviral activityagainst other viruses (herpes simplex viruses 1 and 2, vacciniavirus, varicella-zoster virus, vesicular stomatitis virus, respiratorysyncytial virus, reovirus 1, Sindbis virus, Punta Toro virus, cyto-megalovirus, influenza virus A [subtypes H1N1 and H3N2], in-fluenza virus B, feline coronavirus, and feline herpes virus) did notreveal any inhibitory activity, except when evaluated againstEV71, a virus whose structure and mechanism of replication arecompletely different than those of HIV. This unexpected and in-triguing observation prompted us to investigate in more detail theanti-EV71 activity of this dendrimer family.Dendrimers 1 through 11 (Fig. 1) were first evaluated for se-lective antiviral activity (50% effective concentration [EC50])against the BrCr lab strain of EV71 in a virus-cell-based assay onrhabdomyosarcoma (RD) cells, which are known for their highsusceptibility to EV71-induced cell death (14). Toxicity (50% cy-totoxic concentration [CC50]) was also assessed in a similar assaysetup with treated uninfected cells. Table 1 summarizes the resultsof these evaluations. The capsid binder pirodavir was included asa reference (15, 16). While the antiviral activity against HIV was inthe 2.2 to 16M range, slightly better activity was observed (0.8 to14 M) for EV71.Study of the structure-activity relationship (SAR) led to thefollowing conclusions: (i) the absence of Trp on the periphery isdetrimental for anti-EV71 activity (“nude acids” 10 and 11 wereinactive at EC50s of98 and48 M, respectively); (ii) multiva-lent presentation of Trp is important for anti-EV71 activity (com-pound 9, with only three Trp residues, is inactive, while its respec-tive superior analog, 5, with nine Trp residues is active); (iii) theReceived 21 March 2016 Returned for modification 14 April 2016Accepted 25 May 2016Accepted manuscript posted online 31 May 2016Citation Rivero-Buceta E, Sun L, Martínez-Gualda B, Doyagüez EG, Donckers K,Quesada E, Camarasa M-J, Delang L, San-Félix A, Neyts J, Leyssen P. 2016.Optimization of a class of tryptophan dendrimers that inhibit HIV replication leadsto a selective, specific, and low-nanomolar inhibitor of clinical isolates ofenterovirus A71. Antimicrob Agents Chemother 60:5064–5067.doi:10.1128/AAC.00626-16.Address correspondence to Ana San-Félix, anarosa@iqm.csic.es, orJohan Neyts, johan.neyts@kuleuven.be.E.R.-B. and L.S. contributed equally to this work.This article is dedicated to the memory of Prof. Chris McGuigan.Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.00626-16.Copyright © 2016, American Society for Microbiology. All Rights Reserved.crossmark5064 aac.asm.org August 2016 Volume 60 Number 8Antimicrobial Agents and Chemotherapy on November 7, 2016 by Red de Bibliotecas del CSIChttp://aac.asm.org/Downloaded from presence of 9 or 12 Trp residues on the periphery is sufficient foranti-EV71 activity (compound 6, with 12 Trp residues, was moreactive than compounds 7 and 8, with 15 and 18 Trp residues,respectively); and (iv) the flexibility of the central scaffold does notappear to have a pronounced impact on antiviral activity (com-pounds 1 and 2, with triethylbenzene and benzene rigid cores,respectively, showed activity similar to that of compound 3, with amore flexible cyclohexane core). Interestingly, the SAR that is de-scribed here for EV71 is very similar to that previously reportedfor HIV (13).To take a next step in the exploration of the structure-activityrelationship of this class of compounds, compound 12, which hasa central pentaerythritol scaffold and 12 Trp residues on the pe-riphery, was synthesized (Fig. 1). This compound was preparedusing a strategy similar to that described by Rivero-Buceta et al.(13).Compound 12 proved to be 3-fold more active (EC50, 0.29M) than compounds 5 and 6 (EC50s, 0.9 and 0.8 M, respec-tively), the most active compounds among dendrimers 1 through11, and equally as active as pirodavir, the reference compound(Table 1). Compound 12 also has the highest selectivity index (SIof 103) of the dendrimer series.Subsequently, the antiviral activity of compound 12 was eval-uated in virus-cell-based assays against a panel of representativeFIG 1 Structures of dendrimers 1 through 12.TABLE 1 Antiviral activity of dendrimers against the BrCr lab strain ofEV71 in RD cellsaCompound EC50 (M) CC50 (M) SI1 10 1b 37 3.72 3.5 0.3b 45 2b 133 3.9 0.2b 67 1b 174 39 90 2b ND5 0.9 0.1b 38 426 0.8 0.1b 28 13b 357 1.9 0.1b 32 1b 178 14 1b 22 1b 1.59 120 120 ND10 98 98 ND11 48 48.0 0.2b ND12 0.29 0.07b 30.0 2.5b 10314 42 7b 117 2b 2.8Pirodavir 0.3 0.1b 54 180a All values are a summary of multiple dose-response curves (2) from multipleindependent (1) experiments. CC50, concentration of compound at which a 50%reduction in cell viability is observed; EC50, concentration of compound at which thevirus-induced cytopathic effect is reduced by 50%; SI, selectivity index (CC50/EC50);ND, not determined.b Following microscopic quality control, at least at one concentration of compound, novirus-induced cell death was observed, and the compound did not cause an adverseeffect on the host cell or monolayer morphology.Low Nanomolar Tryptophan Dendrimer Inhibitors of EV71August 2016 Volume 60 Number 8 aac.asm.org 5065Antimicrobial Agents and Chemotherapy on November 7, 2016 by Red de Bibliotecas del CSIChttp://aac.asm.org/Downloaded from enteroviruses (Table 2). Some, but less pronounced, antiviral ac-tivity was detected against echovirus 11 (ECHO11) and enterovi-rus D68 (EV-D68), which indicates that this compound is a quitespecific inhibitor of the replication of EV71.Finally, the antiviral potency of compound 12 was also evalu-ated in virus-cell-based assays against a large panel of clinicalEV71 isolates with strains that belong to different clusters (A, B5,C2, and C4). Strikingly, compound 12 proved to be a 250- to3,800-fold more potent inhibitor of the replication of these virusesthan the BrCr lab strain (Table 3), with EC50s in the low-nanomo-lar/high-picomolar range. To determine at which stage of the vi-rus replication cycle the compound acts, a time-of-drug-additionstudy was performed in which the capsid binder pirodavir and the3C protease inhibitor rupintrivir were indicated on referencecompounds (Fig. 2) (15, 17). Similar to results for pirodavir, clearinhibition of virus replication was observed only when the drugwas added during or before infection. Both compound 12 andpirodavir lost their moderate activity when added after the infec-tion period. This is in line with the observations that the com-pounds inhibit HIV entry. The viral 3C protease inhibitor rupin-trivir lost its activity when added 6 or 7 h after infection, which isin line with its mechanism of action.It can be hypothesized that the mechanism of action in thecontext of EV71 will most involve a glycosylated protein on thehost cell surface because of the following: (i) the structures ofthe two viruses (HIV and EV71) are very different, (ii) the differ-ence in potencies against the clinical isolates versus the laboratorystrain is striking, and (iii) the EV71 virion lacks (in contrast toHIV) glycosylated proteins on its surface This is currently beingexplored further.In summary, a novel class of potent, selective, specific, andearly-stage inhibitors of enterovirus A71 replication has been dis-covered. To consolidate the structure-activity relationship obser-vations, a new dendrimer with a central pentaerythritol scaffoldand 12 Trp residues on the periphery was synthesized. This com-pound proved to be exquisitely active against clinical isolates ofEV71 (belonging to each of the genogroups).Because enterovirus A71 is a virus that is transmitted throughthe fecal-oral route and because the molecular weight of the mol-ecules probably would prevent them from being transferred fromthe gut lumen to the bloodstream following oral administration,one could envisage using this type of compound prophylacticallyto create a chemotherapeutical barrier in the gut to prevent infec-tion with EV71 or using it as a topical cream to treat virus-inducedlesions. However, whether additional modifications can furtherincrease the potency of this compound to obtain a suitable candi-date for proof-of-concept studies should be explored first.ACKNOWLEDGMENTSThis work has been supported by the Spanish MINECO (ProjectSAF2012-39760-C02-01, cofinanced by the FEDER program; Plan Nacio-nal de Cooperación Público-Privada; and Subprograma INNPACTOIPT-2012-0213-060000, cofinanced by the FEDER program) and the Co-munidad de Madrid (BIPEDD2-CM-S2010/BMD-2457). This work wasalso funded by EU FP7 (FP7/2007-2013) Project EUVIRNA under GrantTABLE 2 Evaluation of the broad-spectrum antiviral effect ofcompound 12 against a representative panel of enterovirusesSpecies Virus Host cell EC50 (M)aEnterovirus A Enterovirus A71 BrCr strain RD 0.29 0.07bEnterovirus B Coxsackievirus B3 Nancy strain Vero Ac 28Echovirus 11 Gregory strain BGMd 1.3 0.2bEnterovirus C Poliovirus 1 Sabin strain BGM 28Enterovirus D Enterovirus D68 CU70 strain HeLa Rh 6.0 2.1bRhinovirus A Rhinovirus 2 HeLa Rh 28Rhinovirus B Rhinovirus 14 HeLa Rh 28a All values were obtained from multiple (2) independent (1) experiments.b Following microscopic quality control, at least at one concentration of compound, novirus-induced cell death was observed, and the compound did not cause an adverseeffect on the host cell or monolayer morphology.c Vero cells, African green monkey kidney cells (18).d BGM, Buffalo green monkey cells (19).TABLE 3 Evaluation of the broad-spectrum antiviral effects ofcompound 12 against a representative panel of clinical EV71 isolates inRD cellsEV71 genogroup Virus strain EC50 (nM)aA BrCr 285 70B5 TW/70811/08 0.181 0.020TW/70886/08 0.097 0.039TW/70902/08 0.233 0.081TW/96002/08 0.362 0.081TW/96016/08 0.166 0.055TW/96022/08 0.126 0.04011316 0.385 0.016C2 H08300 461 1.121 0.335H08300 496 0.191 0.040H08326 456 0.181 0.032C4 TW/2728/04 0.075 0.003TW/2429/04 0.301 0.216TW/2639/04 0.079 0.011TW/2815/04 0.158 0.017TW/2824/04 0.400 0.053TW/2871/04 0.226 0.134TW/71595/04 0.666 0.193TW/72232/04 0.199 0.004TW/1956/05 0.229 0.175TW/71428/05 0.301 0.166a All values were obtained from multiple (2) independent (1) experiments.Following microscopic quality control, at least at one concentration of compound, novirus-induced cell death was observed, and the compound did not cause an adverseeffect on the host cell or monolayer morphology.FIG2 Effects of pirodavir (capsid binder), rupintrivir (3C protease inhibitor),and compound 12 in a time-of-drug-addition assay.Rivero-Buceta et al.5066 aac.asm.org August 2016 Volume 60 Number 8Antimicrobial Agents and Chemotherapy on November 7, 2016 by Red de Bibliotecas del CSIChttp://aac.asm.org/Downloaded from 408 Agreement 264286 by EU FP7 SILVER (Contract HEALTH-F3-2010-260644), a grant from the Belgian Interuniversity Attraction Poles (IAP)Phase VII–P7/45 (BELVIR), and the EU FP7 Industry-Academia Partner-ships and Pathways Project AIROPICO. The Spanish MEC/MINECO isalso acknowledged for a grant to E.R.-B. L.S. was funded by China Schol-arship Council (CSC) Grant 201403250056.We also acknowledge Charlotte Vanderheydt for help with the pro-cessing of the antiviral data.FUNDING INFORMATIONThis work, including the efforts of Eva Rivero-Buceta, Elisa G. Doyagüez,Ernesto Quesada, María-José Camarasa, and Ana San-Félix, was fundedby Comunidad de Madrid (BIPEDD2-CM-S2010/BMD-2457). Thiswork, including the efforts of Liang Sun, Kim Donckers, Leen Delang, andJohan Neyts, was funded by EU FP7 SILVER (HEALTH-F3-2010-260644). This work, including the efforts of Eva Rivero-Buceta, wasfunded by the Spanish MEC/MINECO. This work, including the efforts ofLiang Sun, was funded by China Scholarship Council (CSC)(201403250056). This work, including the efforts of Eva Rivero-Buceta,Elisa G. Doyagüez, Ernesto Quesada, María-José Camarasa, and Ana San-Félix, was funded by the Spanish MINECO (SAF2012-39760-C02-01).REFERENCES1. Pourianfar HR, Grollo L. 2015. Development of antiviral agents towardenterovirus 71 infection. J Microbiol Immunol Infect 48:1– 8. http://dx.doi.org/10.1016/j.jmii.2013.11.011.2. Ng Q, He F, Kwang J. 2015. Recent progress towards novel EV71 anti-therapeutics and vaccines. Viruses 7:6441– 6457. http://dx.doi.org/10.3390/v7122949.3. Chan YF, Sam IC, Wee KL, Abubakar S. 2011. Enterovirus 71 in Ma-laysia: a decade later. Neurol Asia 16:1–15.4. LuanYin C, TzouYien L, KuangHung H, YhuChering H, KuangLin L,Chuen H, ShinRu S, HsiaoChen N, MaoSheng H, HueiShyoung W,ChinYun L. 1999. Clinical features and risk factors of pulmonary oedemaafter enterovirus-71-related hand, foot, and mouth disease. Lancet 354:1682–1686. http://dx.doi.org/10.1016/S0140-6736(99)04434-7.5. Alexander JP, Baden L, Pallansch MA, Anderson LJ. 1994. Enterovirus71 infections and neurologic disease—United States, 1977 1991. J InfectDis 169:905–908. http://dx.doi.org/10.1093/infdis/169.4.905.6. McMinn PC. 2002. An overview of the evolution of enterovirus 71 and itsclinical and public health significance. FEMS Microbiol Rev 26:91–107.http://dx.doi.org/10.1111/j.1574-6976.2002.tb00601.x.7. Chang LY, Lin TY, Huang YC, Tsao KC, Shih SR, Kuo ML, Ning HC,Chung PW, Kang CM. 1999. Comparison of enterovirus 71 and coxsack-ie-virus A16 clinical illnesses during the Taiwan enterovirus epidemic,1998. Pediatr Infect Dis J 18:1092–1096. http://dx.doi.org/10.1097/00006454-199912000-00013.8. Chung PW, Huang YC, Chang LY, Lin TY, Ning HC. 2001. Duration ofenterovirus shedding in stool. J Microbiol Immunol Infect 34:167–170.9. Chang LY, Huang LM, Gau SS, Wu YY, Hsia SH, Fan TY, Lin KL,Huang YC, Lu CY, Lin TY. 2007. Neurodevelopment and cognition inchildren after enterovirus 71 infection. N Engl J Med 356:1226 –1234.http://dx.doi.org/10.1056/NEJMoa065954.10. Chen CY, Chang YC, Huang CC, Lui CC, Lee KW, Huang SC. 2001.Acute flaccid paralysis in infants and young children with enterovirus 71infection: MR imaging findings and clinical correlates. AJNR Am J Neu-roradiol 22:200 –205.11. Dong W, Li X, Yang P, Liao H, Wang X, Wang Q. 2016. The effects ofweather factors on hand, foot and mouth disease in Beijing. Sci Rep6:19247. http://dx.doi.org/10.1038/srep19247.12. Mao QY, Wang Y, Bian L, Xu M, Liang Z. 2016. EV71 vaccine, a newtool to control outbreaks of hand, foot and mouth disease (HFMD).Expert Rev Vaccines 15:599 – 606. http://dx.doi.org/10.1586/14760584.2016.1138862.13. Rivero-Buceta E, Doyagüez EG, Colomer I, Quesada E, Mathys L,Noppen S, Liekens S, Camarasa MJ, Pérez-Pérez MJ, Balzarini J. 2015.Tryptophan dendrimers that inhibit HIV replication, prevent virus entryand bind to the HIV envelope glycoproteins gp120 and gp41. Eur J MedChem 106:34 – 43. http://dx.doi.org/10.1016/j.ejmech.2015.10.031.14. Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T,Koike S. 2009. Scavenger receptor B2 is a cellular receptor for enterovirus71. Nat Med 15:798 – 801. http://dx.doi.org/10.1038/nm.1992.15. Tijsma A, Franco D, Tucker S, Hilgenfeld R, Froeyen M, Leyssen P,Neyts J. 2014. The capsid binder vapendavir and the novel protease in-hibitor SG85 inhibit enterovirus 71 replication. Antimicrob Agents Che-mother 58:6990 – 6992. http://dx.doi.org/10.1128/AAC.03328-14.16. Andries K, Dewindt B, Snoeks J, Willebrords R, Van Eemeren K,Stokbroekx R, Janssen PA. 1992. In vitro activity of pirodavir (R 77975),a substituted phenoxy-pyridazinamine with broad-spectrum antipicorna-viral activity. Antimicrob Agents Chemother 36:100 –107. http://dx.doi.org/10.1128/AAC.36.1.100.17. Thibaut HJ, Leyssen P, Puerstinger G, Muigg A, Neyts J, De Palma AM.2011. Towards the design of combination therapy for the treatment ofenterovirus infections. Antiviral Res 90:213–217. http://dx.doi.org/10.1016/j.antiviral.2011.03.187.18. Kandolf R, Ameis D, Kirschner P, Canu A, Hofschneider PH. 1987. Insitu detection of enteroviral genomes in myocardial cells by nucleic acidhybridization: an approach to the diagnosis of viral heart disease. ProcNatl Acad Sci U S A 84:6272– 6276. http://dx.doi.org/10.1073/pnas.84.17.6272.19. Chonmaitree T, Ford C, Sanders C, Lucia HL. 1988. Comparison of cellcultures for rapid isolation of enteroviruses. J Clin Microbiol 26:2576 –2580.Low Nanomolar Tryptophan Dendrimer Inhibitors of EV71August 2016 Volume 60 Number 8 aac.asm.org 5067Antimicrobial Agents and Chemotherapy on November 7, 2016 by Red de Bibliotecas del CSIChttp://aac.asm.org/Downloaded from 

Optimization of a class of tryptophan dendrimers that inhibit HIV replication leads to a selective, specific, and low-nanomolar inhibitor of clinical isolates of enterovirus A71

Abstract

Similar works

Full text

Available Versions

Lirias

Crossref

Digital.CSIC