Rational design of cytotoxic T-cell inhibitors

Document Type

Article

Publication Date

2000

Abstract

This study describes the use of the CD8/major histocompatibility complex (MHC) class I crystal structure as a template for the de novo design of low-molecular-weight surface mimetics. The analogs were designed from a local surface region on the CD8 a-chain directly adjacent to the bound MHC class I, to block the protein associations in the T-cell activation cluster that occur upon stimulation of the cytotoxic T lymphocytes (CTLs). One small conformationally restrained peptide showed dose-dependent inhibition of a primary allogeneic CTL assay while having no effect on the CD4-dependent mixed lymphocyte reaction (MLR). The analog's activity could be modulated through subtle changes in its side chain composition. Administration of the analog prevented CD8-dependent clearance of a murine retrovirus in BALB/c mice. In C57BL/6 mice challenged with the same retrovirus, the analog selectively inhibited the antiviral CTL responses without affecting the ability of the CTLs to generate robust allogeneic responses.

Publication Title

Nature biotechnology

Volume

18

Issue

9

First Page

984

Last Page

988

Comments

This article was published in Nature biotechnology, Volume 18, Issue 9, Pages 984-988.

The published version is available at http://dx.doi.org/10.1038/79487.

Copyright © 2000 NPG.

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