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Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses

Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses
Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses
Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive immune response. Their activity greatly affects the antigenic peptide repertoire presented to cytotoxic T lymphocytes and as a result can regulate cytotoxic cellular responses contributing to autoimmunity or immune evasion by viruses and cancer cells. Therefore, pharmacological regulation of their activity is a promising avenue for modulating the adaptive immune response with possible applications in controlling autoimmunity, in boosting immune responses to pathogens, and in cancer immunotherapy. In this study we exploited recent structural and biochemical analysis of ERAP1 and ERAP2 to design and develop phosphinic pseudopeptide transition state analogs that can inhibit this family of enzymes with nM affinity. X-ray crystallographic analysis of one such inhibitor in complex with ERAP2 validated our design, revealing a canonical mode of binding in the active site of the enzyme, and highlighted the importance of the S2' pocket for achieving inhibitor potency. Antigen processing and presentation assays in HeLa and murine colon carcinoma (CT26) cells showed that these inhibitors induce increased cell-surface antigen presentation of transfected and endogenous antigens and enhance cytotoxic T-cell responses, indicating that these enzymes primarily destroy epitopes in those systems. This class of inhibitors constitutes a promising tool for controlling the cellular adaptive immune response in humans by modulating the antigen processing and presentation pathway.
adaptive immunity, kinetics, major histocompatibility molecules, molecular structure, specificity
0027-8424
1-9
Zervoudi, E.
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Saridakis, E.
2f519471-de48-4850-a986-064b075e9173
Birtley, J.
a01629db-dfe5-444e-b5b0-2e042c8ca340
Seregin, S.
be1102d6-b0b3-4aa4-9270-67f92747a74d
Reeves, E.
bd61ff0c-6555-47fd-884f-74dc6105e846
Kokkala, P.
03e7cf16-fbcd-44fb-b8c3-819b92f07419
Aldhamen, Y.A.
89d02a6b-76d3-4262-ae18-88605cad016a
Amalfitano, A.
8c342168-b4fa-46e6-a1d8-b532557495ef
Mavridis, I.
da7c8848-8789-48f7-84f0-1f51e32bd7a7
James, E.
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Georgiadis, D.
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Stratikos, E.
816fb8a8-a445-486b-aef2-d442a0702afd
Zervoudi, E.
e47c2b11-767b-4ffd-817b-37047a680b67
Saridakis, E.
2f519471-de48-4850-a986-064b075e9173
Birtley, J.
a01629db-dfe5-444e-b5b0-2e042c8ca340
Seregin, S.
be1102d6-b0b3-4aa4-9270-67f92747a74d
Reeves, E.
bd61ff0c-6555-47fd-884f-74dc6105e846
Kokkala, P.
03e7cf16-fbcd-44fb-b8c3-819b92f07419
Aldhamen, Y.A.
89d02a6b-76d3-4262-ae18-88605cad016a
Amalfitano, A.
8c342168-b4fa-46e6-a1d8-b532557495ef
Mavridis, I.
da7c8848-8789-48f7-84f0-1f51e32bd7a7
James, E.
7dc1afb7-d326-4050-89fc-1f4e2a1a19a4
Georgiadis, D.
f4bedada-77a4-4fa5-ba47-53c73fa9ed83
Stratikos, E.
816fb8a8-a445-486b-aef2-d442a0702afd

Zervoudi, E., Saridakis, E., Birtley, J., Seregin, S., Reeves, E., Kokkala, P., Aldhamen, Y.A., Amalfitano, A., Mavridis, I., James, E., Georgiadis, D. and Stratikos, E. (2013) Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses. Proceedings of the National Academy of Sciences, 1-9. (doi:10.1073/pnas.1309781110). (PMID:24248368)

Record type: Article

Abstract

Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive immune response. Their activity greatly affects the antigenic peptide repertoire presented to cytotoxic T lymphocytes and as a result can regulate cytotoxic cellular responses contributing to autoimmunity or immune evasion by viruses and cancer cells. Therefore, pharmacological regulation of their activity is a promising avenue for modulating the adaptive immune response with possible applications in controlling autoimmunity, in boosting immune responses to pathogens, and in cancer immunotherapy. In this study we exploited recent structural and biochemical analysis of ERAP1 and ERAP2 to design and develop phosphinic pseudopeptide transition state analogs that can inhibit this family of enzymes with nM affinity. X-ray crystallographic analysis of one such inhibitor in complex with ERAP2 validated our design, revealing a canonical mode of binding in the active site of the enzyme, and highlighted the importance of the S2' pocket for achieving inhibitor potency. Antigen processing and presentation assays in HeLa and murine colon carcinoma (CT26) cells showed that these inhibitors induce increased cell-surface antigen presentation of transfected and endogenous antigens and enhance cytotoxic T-cell responses, indicating that these enzymes primarily destroy epitopes in those systems. This class of inhibitors constitutes a promising tool for controlling the cellular adaptive immune response in humans by modulating the antigen processing and presentation pathway.

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More information

Published date: 18 November 2013
Keywords: adaptive immunity, kinetics, major histocompatibility molecules, molecular structure, specificity
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 359580
URI: http://eprints.soton.ac.uk/id/eprint/359580
ISSN: 0027-8424
PURE UUID: 1ca226ab-1e39-450e-b3d3-b4e2512298b8
ORCID for E. James: ORCID iD orcid.org/0000-0001-8638-7928

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Date deposited: 05 Nov 2013 10:12
Last modified: 15 Mar 2024 03:26

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Contributors

Author: E. Zervoudi
Author: E. Saridakis
Author: J. Birtley
Author: S. Seregin
Author: E. Reeves
Author: P. Kokkala
Author: Y.A. Aldhamen
Author: A. Amalfitano
Author: I. Mavridis
Author: E. James ORCID iD
Author: D. Georgiadis
Author: E. Stratikos

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