CoChat
Sign Up
Cited by 2Chemical Synthesis and Analysisvaccines and immunoinformatics approachesImmunotherapy and Immune Responses

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Systematic Evaluation of Peptidomimetic Modifications in a Major Histocompatibility Complex Class I Model Epitope: A Framework for Immunogenic Antigen Design

Open access
Newkirk, Sarah E., Kelly, Joey J., Hourn, Nita, Bhandari, Sobika, Spencer, Naomi, Pires, Marcos M.·2026·ACS Chemical Biology
DOI 10.1021/acschembio.6c00291PMC PMC13288458
Open this paper in CoChat — free accountOpen PDF

Abstract

ABSTRACT Peptide-based cancer vaccines offer a promising strategy to target tumor-specific neoantigens. This approach is increasingly critical as post-translationally modified peptides, driven by altered tumor metabolism, emerge as a unique class of neoantigens. Because these chemically distinct epitopes cannot be genetically encoded by mRNA or viral platforms, synthetic peptide vaccines are poised to be the primary route to target these types of neoantigens. Yet, their clinical translation is restricted by poor metabolic stability, limited intracellular permeability, and structural requirements for MHC-I binding and T cell receptor (TCR) recognition. Although peptidomimetic modifications have been widely explored to improve pharmacokinetics, their impact on antigen presentation and immune recognition remains poorly understood. Here, we undertook a comprehensive evaluation of peptidomimetics geared at MHC-I neoantigens and generated a diverse library of systematically modified peptides that incorporate backbone N -methylation, peptoid substitution, and stereochemical inversion. Integrated assays revealed a highly position-dependent tolerance to peptidomimetic modifications, while subsequent combinatorial designs demonstrated non-additive effects on the balance between immunogenicity and pharmacokinetics. Collectively, these findings establish design principles and provide a framework for balancing immune recognition with enhanced stability and permeability in peptidomimetic antigen design.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1021/acschembio.6c00291

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 98

  1. 10.1038/nri3084 · DOI · Paper page
  2. 10.1038/nri1245 · DOI
  3. 10.1126/science.aaa4971 · DOI · Paper page
  4. 10.1016/j.celrep.2018.03.052 · DOI
  5. 10.1016/j.ccell.2018.07.001 · DOI
  6. 10.1038/s41598-019-50738-4 · DOI
  7. 10.1016/j.trecan.2020.04.011 · DOI
  8. 10.1038/s41587-022-01464-2 · DOI
  9. 10.1038/s41392-022-01270-x · DOI · Paper page
  10. 10.1177/2051013614525375 · DOI
  11. 10.1038/nrd2224 · DOI
  12. 10.1097/PPO.0b013e318233e5b2 · DOI
  13. 10.3389/fonc.2021.663264 · DOI
  14. 10.1038/nature22991 · DOI · Paper page
  15. 10.1093/annonc/mdu211 · DOI
  16. 10.1007/s00262-008-0540-3 · DOI
  17. Ohno S., 2012, Anticancer Res., 32, 2263
  18. 10.1158/1078-0432.CCR-17-2169 · DOI
  19. 10.1007/s40262-013-0079-0 · DOI
  20. 10.1021/jacs.1c00016 · DOI · Paper page
  21. 10.1093/intimm/9.11.1701 · DOI
  22. 10.1016/j.addr.2025.115675 · DOI
  23. 10.1111/cbdd.12055 · DOI
  24. 10.1016/j.drudis.2014.10.003 · DOI
  25. 10.1038/s41392-022-00904-4 · DOI · Paper page
  26. 10.1016/j.it.2016.08.010 · DOI · Paper page
  27. 10.1021/acs.bioconjchem.8b00778 · DOI
  28. 10.1038/nri3254 · DOI
  29. 10.1038/32183 · DOI
  30. 10.1084/jem.192.12.1685 · DOI
  31. 10.1084/jem.20020161 · DOI
  32. 10.1007/BF02442589 · DOI
  33. 10.3389/fimmu.2021.637963 · DOI · Paper page
  34. 10.1016/j.tips.2023.04.003 · DOI
  35. 10.1016/j.cbpa.2017.02.006 · DOI
  36. 10.1021/jm0102147 · DOI
  37. 10.1007/s12079-018-0492-0 · DOI
  38. 10.1021/acsomega.4c02604 · DOI
  39. 10.1021/acsomega.1c06964 · DOI
  40. 10.1002/prot.340160309 · DOI · Paper page
  41. 10.1073/pnas.0407677102 · DOI
  42. 10.1073/pnas.94.23.12545 · DOI
  43. 10.1073/pnas.91.21.9765 · DOI
  44. 10.1016/S0161-5890(97)00004-7 · DOI · Paper page
  45. 10.1021/jm9509511 · DOI
  46. 10.1016/j.jaut.2020.102543 · DOI
  47. 10.1021/cb500888q · DOI
  48. 10.1021/jm000909s · DOI · Paper page
  49. 10.1074/jbc.M102772200 · DOI
  50. 10.4049/jimmunol.175.6.3810 · DOI · Paper page
  51. 10.1080/15384047.2025.2486141 · DOI · Paper page
  52. 10.1021/jacs.3c05300 · DOI · Paper page
  53. 10.1021/acschembio.2c00403 · DOI
  54. 10.4049/jimmunol.152.6.2890 · DOI
  55. 10.1074/jbc.270.44.26057 · DOI
  56. 10.1097/00002371-200001000-00015 · DOI
  57. 10.1016/j.molimm.2004.04.019 · DOI
  58. 10.1093/intimm/10.2.159 · DOI
  59. Ettouati L., 1996, Pept Res., 9, 248
  60. 10.1016/S0196-9781(02)00148-1 · DOI · Paper page
  61. 10.1074/jbc.274.15.10227 · DOI
  62. 10.1002/psc.311 · DOI
  63. 10.4049/jimmunol.167.10.5852 · DOI
  64. 10.4049/jimmunol.1400800 · DOI
  65. 10.1021/acschembio.0c00218 · DOI
  66. 10.1021/acs.jmedchem.3c01140 · DOI
  67. 10.3390/md19060311 · DOI · Paper page
  68. 10.1016/j.chembiol.2011.06.006 · DOI
  69. 10.1038/s42004-026-01898-8 · DOI
  70. 10.4049/jimmunol.150.7.2724 · DOI
  71. 10.1038/346476a0 · DOI
  72. 10.1016/0092-8674(90)90020-F · DOI
  73. 10.1002/eji.1830210915 · DOI
  74. 10.1016/0022-1759(93)90210-X · DOI
  75. 10.1016/j.vetimm.2012.08.012 · DOI
  76. 10.1016/S0021-9258(19)36925-X · DOI
  77. 10.1073/pnas.92.7.2479 · DOI
  78. 10.1002/eji.1830221028 · DOI
  79. 10.1021/acspolymersau.2c00036 · DOI
  80. 10.1021/ja00052a076 · DOI
  81. 10.1016/S0968-0896(01)00434-5 · DOI
  82. 10.1529/biophysj.106.095208 · DOI
  83. 10.1172/JCI91512 · DOI
  84. 10.1073/pnas.88.9.3972 · DOI
  85. 10.1073/pnas.89.13.6020 · DOI
  86. 10.1101/2025.11.06.687013 · DOI
  87. 10.1021/acschembio.4c00312 · DOI · Paper page
  88. 10.1038/s41467-026-68717-5 · DOI
  89. 10.1073/pnas.0708254105 · DOI
  90. 10.1021/acs.orglett.5b01162 · DOI
  91. 10.1073/pnas.89.20.9367 · DOI
  92. 10.1016/j.bmc.2008.04.074 · DOI
  93. 10.1021/acschembio.5b00189 · DOI
  94. 10.1039/C4MD00409D · DOI
  95. 10.1016/j.peptides.2005.06.015 · DOI
  96. 10.1021/ar8000603 · DOI · Paper page
  97. 10.3390/ph15101283 · DOI
  98. 10.1007/s00726-005-0289-3 · DOI

Metadata

Authors
Newkirk, S. E., Kelly, J. J., Hourn, N., Bhandari, S., Spencer, N., & Pires, M. M.
Affiliations
University of Virginia (US)
Corresponding author
Pires, Marcos M.
ORCID
Venue
ACS Chemical Biology
Publisher
American Chemical Society (ACS)
Published
2026-05-26
Volume
21
Issue
6
Pages
1533-1546
ISSN
  • 1554-8929 (ISSN-L)
  • 1554-8937
DOI
10.1021/acschembio.6c00291
PMC
PMC13288458
OpenAlex
W7162420473
Cited by
2
References
1
Citations by year
2026: 2
FWCI
3.20
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Chemical Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (submittedVersion)
Funders
National Institute of General Medical Sciences (R35GM124893)
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
peptidomimetics, MHC class I epitopes, methylation, stereochemical inversion, immunogenicity, pharmacokinetics, combinatorial designs, peptide stability, peptide permeability

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review