NDLI: Targeted delivery of antigen processing inhibitors to antigen presenting cells via mannose receptors

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Targeted delivery of antigen processing inhibitors to antigen presenting cells via mannose receptors

Content Provider	PubMed Central
Author	Raiber, Eun-ang Calogero, Tulone Zhang”, Yanjing Luisa, Martinez-pomares Steed, Emily Sponaas, Anna M. Langhorne, Jean Mahdad, Noursadeghi Chain, Benjamin M. Tabor, Alethea B.
Abstract	Improved chemical inhibitors are required to dissect the role of specific antigen processing enzymes and to complement genetic models. In this study we explore the in vitro and in vivo properties of a novel class of targeted inhibitor of aspartic proteinases, in which pepstatin is coupled to mannosylated albumin (MPC6), creating an inhibitor with improved solubility and the potential for selective cell tropism. Using these compounds, we have demonstrated that MPC6 is taken up via mannose receptor facilitated endocytosis, leading to a slow but continuous accumulation of inhibitor within large endocytic vesicles within dendritic cells, and a parallel inhibition of intracellular aspartic proteinase activity. Inhibition of intracellular proteinase activity is associated with reduction in antigen processing activity, but this is epitope specific, preferentially inhibiting processing of T cell epitopes buried within compact proteinase-resistant protein domains. Unexpectedly, we have also demonstrated, using quenched fluorescent substrates, that little or no cleavage of the disulfide linker takes place within dendritic cells, but this does not appear to affect the activity of MPC6 as an inhibitor of cathepsins D and E in vitro and in vivo. Finally, we have shown that MPC6 selectively targets dendritic cells and macrophages in spleen in vivo. Access to non-lymphoid tissues is very limited in the steady state, but is strongly enhanced at local sites of inflammation. The strategy adopted for MPC6 synthesis may therefore represent a more general way to deliver chemical inhibitors to cells of the innate immune system, especially at sites of inflammation.
Related Links	http://dx.doi.org/10.1021/cb100008p
Ending Page	476
Page Count	16
Starting Page	461
File Format	PDF
ISSN	15548929
e-ISSN	15548937
Journal	ACS chemical biology
Issue Number	5
Volume Number	5
Language	English
Publisher Date	2010-05-21
Access Restriction	Open
Subject Keyword	Molecular Medicine Biochemistry Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine Biochemistry Molecular Medicine

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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