Analysis of in vivo immunosuppressive and in vitro interaction with constitutive heat shock protein 70 activity of LF08-0299 (Tresperimus) and analogues.
LF08-0299 (Tresperimus) is a new immunosuppressive analogue of Gusperimus (15-deoxyspergualin or DSG). Despite the fact that its mechanism of action remains unknown, DSG has previously been demonstrated to bind specifically to Hsc70 protein, a constitutive or cognate member of heat shock protein 70 family. Herein we further explore whether immobilised LF08-0299 will selectively retain the heat shock protein Hsc70. We analysed the correlation between biological activity in vivo in the prevention of murine graft-vs-host disease (GVHD) and the ability in vitro in dissociating Hsc70 from LF08-0299 resin for LF08-0299 and structural analogues. The Hsc70 protein bound to the LF08-0299 immobilised specifically via the spermidine primary amino group and could be successfully eluted from the column by various analogues of LF08-0299. All immunosuppressants tested were able to competitively bind Hsc70 although some biological inactive compounds could as well. Our data suggests that LF08-0299 and its active analogue effects were not mediated directly through the interaction of molecules with Hsc70. The mechanism of action probably occurred by more than one step, the first being the binding of Hsc70.
Komesli
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Département d'immunologie, Laboratoires Fournier SA, Daix, France. s.komesli@fournier.fr
Dumas
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C
Dutartre
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D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000378:metabolism* / Q000627:therapeutic use*; D002846:Chromatography, Affinity; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000627:therapeutic use*; D019169:Jurkat Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D011485:Protein Binding; D011817:Rabbits; D013329:Structure-Activity Relationship
D002219:Carbamates; D018840:HSP70 Heat-Shock Proteins; D007166:Immunosuppressive Agents; C092303:tresperimus