A5,a New Small-Molecule Inhibitor of CD4 D1 Obtained from a Computer-Aided Screening Method,Contributes to the Inhibition of CD4 + T-cell Function

Abstract

In this study, the authors apply a computer-based strategy to screen thousands of small-molecule, nonpeptidic organic compounds in the Available Chemicals Directory database and to select a series of potential candidates as ligands of the proposed CD4 D1 surface pocket. Then, several cell-based models are used to determine the actual biological functions of these compounds. A small molecule designated A5 (N-((pyridine-4-yl)methylene)thiophene-2-carbohydrazide) was obtained by a virtual screening followed by 3 cell-based functional assays. The results show that A5 could specifically block the CD4—major histocompatibility complex II binding in a rosetting assay, inhibit the mixed lymphocyte reaction—induced T-cell proliferation in a concentration-dependent manner, and reduce the PMA plus ionomycin—stimulated interleukin-2 secretion from peripheral blood mononuclear cells. (Journal of Biomolecular Screening 2007:800-808)

Keywords

CD4—MHC II interaction computer-aided screening novel CD4 D1 inhibitor cell-based functional assays

References

Janin J. , Chothia C. : The structure of protein-protein recognition sites . J Biol Chem 1990;265: 16027-16030 .

Davies DR , Padlan EA , Sheriff S. : Antibody-antigen complexes . Annu Rev Biochem 1990;59: 439-473 .

Littman DR : The structure of the CD4 and CD8 genes . Annu Rev Immunol 1987;5: 561-584 .

Wang J. , Yan Y. , Garrett Tpj , Liu J. , Rodgers DW , Garlick RL , et al: Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains . Nature 1990;348: 411-418 .

Wu H. , Kwong PD , Hendrickson WA : Dimeric association and segmental variability in the structure of human CD4 . Nature (London) 1997;387: 527-530 .

Moebius U. , Clayton LK , Abraham S. , Diener A. , Yunis JJ , Harrison SC : Human immunodeficiency virus gp120 binding C′C″ ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A 1992;89:12008-12012.

Moebius U. , Pallai P. , Harrison SC , Reinherz EL : Delineation of an extended surface contact area on human CD4 involved in class II major histocompatibility complex binding . Proc Natl Acad Sci U S A 1993;90: 8259-8263 .

Leahy DJ : A structural view of CD4 and CD8 . FASEB J 1995;9: 17-25 .

Li S. , Gao J. , Satoh T. , Friedman T. , Edling A. , Koch U. , et al: A computer screening approach to immunoglobulin superfamily structures and interactions: discovery of small non-peptidic CD4 inhibitors as novel immunotherapeutics . Proc Natl Acad Sci U S A 1997;94: 73-78 .

10.

Jameson BA , McDonnell JM , Marini JC , Korngold R. : A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis . Nature 1994;368: 744-746 .

11.

Friedman TM , Reddy AP , Wassell R. , Jameson BA , Korngold R. : Identification of a human CD4-CDR3-like surface involved in CD4+ T cell function . J Biol Chem 1996;271: 22635-22640 .

12.

Satoh T. , Aramini JM , Li S. , Friedman TM , Gao J. , Edling A. , et al: Bioactive peptide design based on protein surface epitopes: a cyclic heptapeptide mimics CD4 domain 1 CC′ loop and inhibits CD4 biological function . J Biol Chem 1997;272: 12175-12180 .

13.

Meng EC , Shoichet BK , Kuntz ID : Automated docking with grid-based energy evaluation . J Comput Chem 1992;13: 505-524 .

14.

Ring CS , Sun E. , McKerrow JH , Lee GK , Rosenthal PJ , Kuntz ID , et al: Structure-based inhibitor design by using protein models for the development of antiparasitic agents . Proc Natl Acad Sci U S A 1993;90: 3583-3587 .

15.

Xiao H. , Feng JN , He XH , Zhang H. , Zhang JR , Zhang L. , et al: Potent inhibition of the CD4-dependent T cell response by J2, a novel nonpeptide organic ligand of CD4 D1 . Mol Immunol 2007;44: 784-795 .

16.

Xiao H. , Zhang H. , Yu ZY , Zhang L. , Yu M. , Huang YF , et al: J2 prolongs the corneal allograft survival through inhibition of the CD4+ T cell-mediated response in vivo . Transpl Immunol. Forthcoming.