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Evaluation of the antiretroviral effects of a PEG-conjugated peptide derived from human CD38

AuthorsBensi, Thea; Mele, Federico; Ferretti, Massimo; Norelli, Sandro; El Daker, Sary; Chiocchetti, Annalisa; Rojo, José María ; Cauda, Roberto; Dianzani, Umberto; Savarino, Andrea
MTT assay
protein-protein interaction
therapeutic peptide
Issue DateFeb-2009
PublisherInforma Healthcare
CitationExpert Opinion on Therapeutic Targets, 13 (2) : 141-152 (2009)
AbstractObjective: Cell infection by HIV-1 is inhibited by both the expression of CD38 and a soluble peptide (sCD38p) corresponding to its extracellular membrane-proximal amino acid sequence (amino acids 51 - 74). We show here the effects of PEG conjugation to sCD38p and provide new insights into the mechanisms behind the anti-HIV-1 effects of CD38 and derived peptides. Research design/methods: In-vitro and in-silico study. Results: PEGylation of sCD38p increased its ability to inhibit replication of HIV-1 in MT-4 cells and syncytia formation in cocultures of MT-2 and persistently HIV-1IIIB-infected H9IIIB cells. In silico modeling suggests that sCD38p and CD4 form stable heterodimers involving, among others, an interaction between lysine 57 (K57) of CD38 and a groove in the CD4 receptor, which, in CD4/gp120 complexes, is partially occupied by a lysine residue of the HIV-1 envelope glycoprotein. K57 substitution with a glycine in sCD38p impaired its ability to inhibit syncytia formation in MT-2/H9IIIB cell cocultures and gp120 binding to CD4 in a mouse T cell line expressing human but not mouse CD4. Conclusions: PEGylation significantly improves the anti-HIV-1 activity of sCD38p, whose effect is probably due to competition with gp120 for a common binding site on CD4 although other mechanisms cannot be excluded so far. The inhibitory concentrations of the sCD38p-PEG as well as its poor toxicity, merit further consideration in anti-HIV-1 strategies
Description12 páginas -- PAGS nros. 141-152
Publisher version (URL)http://dx.doi.org/10.1517/14728220802637147
Appears in Collections:(CIB) Artículos
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