OBJECTIVE: 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-1(IIIB)-infected H9(IIIB) 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/H9(IIIB) 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.

Bensi, T., Mele, F., Ferretti, M., Norelli, S., El Daker, S., Chiocchetti, A., Maria Rojo, J., Cauda, R., Dianzani, U., Savarino, A., Evaluation of the antiretroviral effects of a PEG-conjugated peptide derived from human CD38, <<EXPERT OPINION ON THERAPEUTIC TARGETS>>, 2009; (Febbraio): 141-152 [http://hdl.handle.net/10807/7570]

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

J; Cauda;
2009

Abstract

OBJECTIVE: 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-1(IIIB)-infected H9(IIIB) 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/H9(IIIB) 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.
Inglese
Bensi, T., Mele, F., Ferretti, M., Norelli, S., El Daker, S., Chiocchetti, A., Maria Rojo, J., Cauda, R., Dianzani, U., Savarino, A., Evaluation of the antiretroviral effects of a PEG-conjugated peptide derived from human CD38, <<EXPERT OPINION ON THERAPEUTIC TARGETS>>, 2009; (Febbraio): 141-152 [http://hdl.handle.net/10807/7570]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/7570
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