Antibody Complementarity-Determining Regions (CDRs) Can Display Differential Antimicrobial, Antiviral and Antitumor Activities

Antibody Complementarity-Determining Regions (CDRs) Can Display Differential Antimicrobial, Antiviral and Antitumor Activities

Autor Polonelli, Luciano Google Scholar
Ponton, Jose Google Scholar
Elguezabal, Natalia Google Scholar
Dolores Moragues, Maria Google Scholar
Casoli, Claudio Google Scholar
Pilotti, Elisabetta Google Scholar
Ronzi, Paola Google Scholar
Dobroff, Andrey S. Autor UNIFESP Google Scholar
Rodrigues, Elaine G. Autor UNIFESP Google Scholar
Juliano, Maria A. Autor UNIFESP Google Scholar
Maffei, Domenico Leonardo Google Scholar
Magliani, Walter Google Scholar
Conti, Stefania Google Scholar
Travassos, Luiz R. Autor UNIFESP Google Scholar
Instituição Univ Parma
Univ Basque Country
Univ Milan
Univ Studi Parma
Universidade Federal de São Paulo (UNIFESP)
Resumo Background: Complementarity-determining regions (CDRs) are immunoglobulin (Ig) hypervariable domains that determine specific antibody (Ab) binding. We have shown that synthetic CDR-related peptides and many decapeptides spanning the variable region of a recombinant yeast killer toxin-like antiidiotypic Ab are candidacidal in vitro. An alanine-substituted decapeptide from the variable region of this Ab displayed increased cytotoxicity in vitro and/or therapeutic effects in vivo against various bacteria, fungi, protozoa and viruses. the possibility that isolated CDRs, represented by short synthetic peptides, may display antimicrobial, antiviral and antitumor activities irrespective of Ab specificity for a given antigen is addressed here.Methodology/Principal Findings: CDR-based synthetic peptides of murine and human monoclonal Abs directed to: a) a protein epitope of Candida albicans cell wall stress mannoprotein; b) a synthetic peptide containing well-characterized B-cell and T-cell epitopes; c) a carbohydrate blood group A substance, showed differential inhibitory activities in vitro, ex vivo and/or in vivo against C. albicans, HIV-1 and B16F10-Nex2 melanoma cells, conceivably involving different mechanisms of action. Antitumor activities involved peptide-induced caspase-dependent apoptosis. Engineered peptides, obtained by alanine substitution of Ig CDR sequences, and used as surrogates of natural point mutations, showed further differential increased/unaltered/decreased antimicrobial, antiviral and/or antitumor activities. the inhibitory effects observed were largely independent of the specificity of the native Ab and involved chiefly germline encoded CDR1 and CDR2 of light and heavy chains.Conclusions/Significance: the high frequency of bioactive peptides based on CDRs suggests that Ig molecules are sources of an unlimited number of sequences potentially active against infectious agents and tumor cells. the easy production and low cost of small sized synthetic peptides representing Ig CDRs and the possibility of peptide engineering and chemical optimization associated to new delivery mechanisms are expected to give rise to a new generation of therapeutic agents.
Idioma Inglês
Financiador Department of Education, Universities and Research, Basque Goverment
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Istituto Superiore di Sanita, National Research Project on A.I.D.S.
Cariparma Banking Foundation
Brazilian National Research Council
Número do financiamento Department of Education, Universities and Research, Basque Goverment: IT-264-07
FAPESP: 06/50634-2
Istituto Superiore di Sanita, National Research Project on A.I.D.S.: 50G.30
Istituto Superiore di Sanita, National Research Project on A.I.D.S.: 40D.14
Cariparma Banking Foundation: 2004.0190
Brazilian National Research Council: research fellowship
Data de publicação 2008-06-11
Publicado em Plos One. San Francisco: Public Library Science, v. 3, n. 6, 9 p., 2008.
ISSN 1932-6203 (Sherpa/Romeo, fator de impacto)
Publicador Public Library Science
Extensão 9
Fonte http://dx.doi.org/10.1371/journal.pone.0002371
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000263248800013
Endereço permanente http://repositorio.unifesp.br/handle/11600/30729

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