Modifications in the branched arms of a class of dual inhibitors of HIV and EV71 replication expand their antiviral spectrum.
Antiviral Agents
/ chemical synthesis
Dendrimers
/ chemistry
Dose-Response Relationship, Drug
Enterovirus A, Human
/ drug effects
HIV-1
/ drug effects
Humans
Molecular Structure
Structure-Activity Relationship
Tryptophan
/ chemistry
Viral Envelope Proteins
/ metabolism
Virus Attachment
/ drug effects
Virus Internalization
/ drug effects
Virus Replication
/ drug effects
Viruses
/ classification
AIDS
Antiviral agents
EV71
HIV
HSV-2
Tryptophan
Journal
Antiviral research
ISSN: 1872-9096
Titre abrégé: Antiviral Res
Pays: Netherlands
ID NLM: 8109699
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
24
10
2018
revised:
31
05
2019
accepted:
03
06
2019
pubmed:
23
6
2019
medline:
13
6
2020
entrez:
23
6
2019
Statut:
ppublish
Résumé
We have previously reported a new class of dendrimers with tryptophan (Trp) residues on the surface that show dual antiviral activities against HIV and enterovirus EV71. The prototype compound of this family is a derivative of pentaerythritol with 12 peripheral Trp groups and trivalent spacer arms. Here a novel series of dendrimers with divalent and tetravalent branched arms, instead of the trivalent ones present on the prototype, has been synthesized and its activity against HIV, EV71 and a panel of 16 different viruses and other pathogens has been determined. Convergent or divergent approaches have been used for the synthesis of these compounds. Our findings demonstrate that only compounds with tetravalent branched arms showed the same anti-HIV and anti-EV71 activity of the prototype (low micromolar) and even gain significant antiviral activity against new pathogens such as HSV-2, adenovirus-2, human corona virus and respiratory syncytial virus, being the first members of the Trp dendrimer family that showed activity against those viruses. As the prototype, these compounds also showed low-nanomolar activity against a representative EV71 clinical isolate. Experimental work carried on to determine the mode of action of the most potent IIa, containing tetravalent branched arms, demonstrated that it interacts with the viral envelopes of HIV, EV71 and HSV-2 and thus may prevent virus attachment to the host cell. These results support the interest of this new series of Trp dendrimers and qualify them as useful prototypes for the development of novel inhibitors of viral entry with broad antiviral spectrum.
Identifiants
pubmed: 31228490
pii: S0166-3542(18)30652-1
doi: 10.1016/j.antiviral.2019.06.006
pmc: PMC7114229
pii:
doi:
Substances chimiques
Antiviral Agents
0
Dendrimers
0
Viral Envelope Proteins
0
Tryptophan
8DUH1N11BX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
210-214Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
Références
J Med Toxicol. 2014 Mar;10(1):26-39
pubmed: 23963694
Clin Microbiol Rev. 2016 Jul;29(3):695-747
pubmed: 27281742
Curr HIV Res. 2012 Apr;10(3):228-37
pubmed: 22384842
Lancet. 2003 May 10;361(9369):1577-8
pubmed: 12747873
J Med Chem. 2016 Apr 14;59(7):2849-78
pubmed: 26509831
Curr Opin Virol. 2017 Jun;24:46-54
pubmed: 28437703
FEMS Microbiol Rev. 2002 Mar;26(1):91-107
pubmed: 12007645
Curr Opin HIV AIDS. 2018 Jul;13(4):341-345
pubmed: 29771694
J Med Chem. 2010 Jan 28;53(2):521-38
pubmed: 19785437
Nat Med. 2009 Jul;15(7):798-801
pubmed: 19543282
Nat Rev Microbiol. 2013 Dec;11(12):877-83
pubmed: 24162027
Curr Top Med Chem. 2016;16(10):1074-90
pubmed: 26324044
Drug Des Devel Ther. 2015 Oct 01;9:5447-68
pubmed: 26491256
Curr Opin HIV AIDS. 2018 Jul;13(4):291-293
pubmed: 29702493
Antimicrob Agents Chemother. 2014 Nov;58(11):6990-2
pubmed: 25199773
Lancet Infect Dis. 2010 Nov;10(11):778-90
pubmed: 20961813
Curr Pharm Des. 2013;19(10):1784-99
pubmed: 23092280
Curr Pharm Des. 2013;19(10):1767-83
pubmed: 23092282
Cell Microbiol. 2012 Aug;14(8):1183-92
pubmed: 22583677
AIDS. 2019 Jan 27;33(1):1-11
pubmed: 30096076
J Virol. 2007 Jan;81(1):362-73
pubmed: 17050611
Proc Natl Acad Sci U S A. 1988 Aug;85(16):6132-6
pubmed: 2457906
Adv Exp Med Biol. 2012;726:223-42
pubmed: 22297516
Viral Immunol. 2015 Dec;28(10):546-55
pubmed: 26331265
Antiviral Res. 2010 Jan;85(1):1-18
pubmed: 20018391
J Lab Physicians. 2016 Jan-Jun;8(1):5-18
pubmed: 27013807
Antimicrob Agents Chemother. 1992 Jan;36(1):100-7
pubmed: 1317142
Curr Opin Pharmacol. 2014 Oct;18:1-8
pubmed: 24993074
Annu Rev Med. 2019 Jan 27;70:137-150
pubmed: 30355266
J Antimicrob Chemother. 2014 Aug;69(8):2032-42
pubmed: 24788658
Protein Cell. 2013 Feb;4(2):86-102
pubmed: 23479426
Curr Opin HIV AIDS. 2019 Mar;14(2):143-149
pubmed: 30562177
Eur J Med Chem. 2015 Dec 1;106:34-43
pubmed: 26513643
Lancet. 2010 Jul 3;376(9734):49-62
pubmed: 20609987
Antimicrob Agents Chemother. 2016 Jul 22;60(8):5064-7
pubmed: 27246775
Crit Care Med. 2013 Jul;41(7):1821-2
pubmed: 23774351
PLoS Pathog. 2019 May 9;15(5):e1007760
pubmed: 31071193
Cold Spring Harb Perspect Med. 2012 Apr;2(4):a007161
pubmed: 22474613
Nat Rev Microbiol. 2018 Jun;16(6):368-381
pubmed: 29626210
Top Antivir Med. 2018 Apr;25(4):127-132
pubmed: 29689540
Antiviral Res. 2017 Mar;139:32-40
pubmed: 28017762
J Med Chem. 2018 Jan 11;61(1):62-80
pubmed: 29271653