bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements
Abstract
1. Introduction
Targeted Covalent Inhibitors (TCI) as Potential Antibody Replacements
2. History and General Principle of bioTCI
2.1. From Small Molecular TCI to bioTCI
2.2. Warhead Design and Introduction into Middle/Macro-Biomolecules
2.3. Pros and Cons of bioTCI over Non-Covalent Biomolecular Targeted Inhibitors
3. Recent Hot Topics of bioTci
3.1. Combinatorial Screening of Peptidic TCI: A Well-Developed Modality
3.2. Nucleotidic TCI: A Developing Modality
4. Future Perspectives of bioTCI Research: Technical Challenges and Critical Questions That Need to Be Answered
4.1. Design and Selection Methodology of bioTCI
4.2. Beyond the Target Affinity/Specificity: Additional Functionalization of bioTCI
4.3. Other Possibilities
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADE: | adverse drug effect |
AFS: | aryl-fluorosulfate (aryl-OSO2F) |
bioTCI: | biomolecular targeted covalent inhibitor |
CD: | cluster of differentiation |
CHO: | Chinese hamster ovary |
CS: | complimentary strand |
CuAAC: | copper(I)-catalyzed azide-alkyne cycloaddition |
Da: | Dalton |
DS: | double strand |
EdUTP: | 5-ethynyl-dUTP |
EGFR: | epidermal growth factor receptor |
ELISA: | enzyme-linked immunosorbent assay |
Fab: | fragment antigen binding (variable) |
FasL: | Fas ligand (CD95L, CD178) |
Fc: | fragment crystallizable (constant) |
FcR: | Fc receptor |
FDA: | Food and Drug Administration (USA |
GPCR: | G-protein-coupled receptor |
HER2: | human epidermal growth factor 2 |
mAb: | monoclonal antibody |
NK: | natural killer |
NGS: | next-generation sequencing |
OctdU: | octadiynyl-dU |
PCR: | polymerase chain reaction |
PD1: | programmed cell death protein 1 (CD279) |
PD-L1: | programmed death-ligand 1 (CD274) |
PK: | pharmacokinetic |
PPI: | protein-protein interaction |
PS: | phosphorothioate |
RBD: | receptor binding domain |
SARS-CoV-2: | severe acute respiratory syndrome-associated coronavirus-2 |
SELEX: | Systematic Evolution of Ligands by EXponential enrichment |
SN2: | bimolecular nucleophilic substitution |
SNAr: | nucleophilic aromatic substitution |
SuFEx: | sulfur (VI) fluoride exchange |
SDS: | sodium dodecyl sulfate |
TBA: | thrombin binding aptamer |
TCI: | targeted covalent inhibitor |
TeTCI: | tethered targeted covalent inhibitor |
TRAIL: | TNF-related apoptosis-inducing ligand |
Uaa: | unnatural amino acid |
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Properties | Antibody | Peptide | Nucleotide |
---|---|---|---|
Molecular mass | ~150 kDa for IgG | variable (~110Da/residue) | variable (~340Da/residue) |
Production | complex biologic | Synthetic | Synthetic |
Mechanisms of target elimination | multiple | neutralization | neutralization |
Combinatorial screening | limited | yes | limited |
In vivo half-life | long | Short | extremely short |
Reversibility | no | yes | yes (on-demand) |
Immunogenicity | yes | depends | low |
Generation | Lead Pharmacophore | Obtained Function by Lead Engineering | Warhead Incorporated | Breakthrough Point |
---|---|---|---|---|
1st: Charlton, 1997 | Low molecule; TCI | Increasing affinity/specificity by DNA library conjugation | valyl phosphonate |
|
2nd: Tabuchi, 2021 | Middle molecule; non-covalent DNA aptamer | Nuclease resistance by targeted covalent binding via warhead introduction | 4-(acetyl)-benzene-1- sulfonyl fluoride |
|
2nd: Tivon (2021) | “ | “ | acyl-sulfonamide |
|
2nd: Qin (2021) | “ | “ | 4-(methyl)-benzene-1- sulfonyl fluoride |
|
Molecular Target | Name | mAb | Aptamer | Reference | |
---|---|---|---|---|---|
Check point proteins | |||||
4-1BB | TNF ligand superfamily member 9 | Utomilumab * | M12-23 | [107] | |
B7-H3 | B7 homolog 3 | Enoblituzumab * | none | ||
BLTA | B and T lymphocyte attenuator | Icatolimab * | none | ||
CTLA-4 | cytotoxic T lymphocyte-associate antigen 4 | Ipilimumab, Tremelimumab | aptCTLA-4 | [108,109] | |
ICOS | inducible costimulatory | Vopratelimab * | MRP1-ICOS | [110] | |
Lag-3 | lymphocyte-activation gene 3 | Relatimab | Apt1 | [111] | |
PD1 | programmed cell death protein 1 | Cemiplimab, Dostarlimab, Nivolumab | MP7 | [112,113,114,115] | |
PD-L1 | programmed death ligand 1 | Atezolizumab, Avelumab, Durvalumab | aptPD-L1 | [116,117,118,119,120,121,122,123,124] | |
TIGIT | T cell immunoreceptor with IgG and ITIM domains | Tirabolumab * | none | ||
TIM-3 | T cell immunoglobulin mucin 3 | Sabatolimab *, Cobolimab * | TIJM3Apt | [125,126] | |
Cytokines/Chemokine | |||||
BAFF | B-cell activating factor | Belimumab | R1-14 | [127] | |
IL1b | interleukin 1 beta | Canakinumab | AptIL-1b, many | [128] | |
IL2 | interleukin 2 | Basiliximab, Reslizumab | M20 (@mouse) | [129] | |
IL5 | interleukin 5 | Mepolizumab, Reslizumab | 19 clones in 5 families | [130] | |
IL6 | interleukin 6 | Tocilizumab | S1025, S1026, AIR-3 | [131,132,133] | |
IL12 | interleukin 12 | Ustekinumab | none | ||
IL-13 | interleukin 13 | Tralokinumab | none | ||
IL17a | interleukin 17a | Ixekizumab, Secukinumab | Apt21-2 | [134] | |
IL23 | interleukin 23 | Guselkumab, Tildrakizumab | clone 1, clone A5, C3 | [135,136,137] | |
IL36 | interleukin | Spesolimab | none | ||
TNFa | tumor necrosis factor alpha | Adalimumab, Certolizumab, Golimumab | AptTNF-a, VR11 | [128,138] | |
Tumor markers | |||||
CD3 | cluster of differentiation | 3 | Teplizumab * | J7, OSJ-T1-4 | [139] |
CD4 | “ | 4 | Ibalizumab | U26 | [140] |
CD19 | “ | 19 | Tafasitamab, Blinatumomab | B83.T2 | [141] |
CD20 | “ | 20 | Rituximab, Ibritumomab, Obinutuzumab | AP1-3 | [142] |
CD22 | “ | 22 | Inotuzumab, Moxetunomab, epcortamab * | none | |
CD30 | “ | 30 | Brentuximab | C2, NGS6.0 | [143] |
CD33 | “ | 33 | Gemtuzumab | S30 | [144] |
CD38 | “ | 38 | Daratumumab, Isatuximab | aptamer#1 | [145] |
CD52 | “ | 52 | Alzetuzumab | none | |
CD79b | “ | 79b | Polatuzumab | none | |
GD2 | disialogangloside 2 | Dinutuximab, Naxitamab, Margetuximab | DB67 | [146] | |
Growth factors/receptor | |||||
a-beta | amyloid protein beta | Donanemab * | Ab-Apt, RNV95 | [147,148] | |
CGRP | calcitonin gene-related peptide | Eptinezumab, Frenenezumab, Galcanezumab | Star-F12 | [149] | |
HER2 | human epidermal growth factor receptor 2 | Trastuzumab, Pertuzumab, Margetuximab | HB5, HeA2_3 | [150,151,152,153] | |
PDGFR-a | platelet-derived growth factor receptor alpha | Olaratumab | PDR3 | [154] | |
VEGF | vascular endothelial growth factor | Bevacozumab, Ranibizumab, Brolucizumab | SL2b, many more | [155,156] | |
VEGFR2 | vascular endothelial growth factor receptor 2 | Ramucrumab | Apt01, 02, NX1838 | [157,158] | |
Factor IXa/X | X coagulation factor IXa/X | 5Epicizamab | 9.3t, RB006 | [159] | |
vWF | Von Willebrand factor | Caplacizumab | ARC1779 | [160] |
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Yang, J.; Tabuchi, Y.; Katsuki, R.; Taki, M. bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements. Int. J. Mol. Sci. 2023, 24, 3525. https://doi.org/10.3390/ijms24043525
Yang J, Tabuchi Y, Katsuki R, Taki M. bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements. International Journal of Molecular Sciences. 2023; 24(4):3525. https://doi.org/10.3390/ijms24043525
Chicago/Turabian StyleYang, Jay, Yudai Tabuchi, Riku Katsuki, and Masumi Taki. 2023. "bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements" International Journal of Molecular Sciences 24, no. 4: 3525. https://doi.org/10.3390/ijms24043525
APA StyleYang, J., Tabuchi, Y., Katsuki, R., & Taki, M. (2023). bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements. International Journal of Molecular Sciences, 24(4), 3525. https://doi.org/10.3390/ijms24043525