Recent Advances and Trends in Chemical CPP–Drug Conjugation Techniques
Abstract
:1. Introduction
2. Amide Bond Formation and Related Chemistry
2.1. CPP–Drug Conjugates Comprising a Classical Amide Bond
2.2. CPP–Metal Complex Conjugates
3. CPP–Drug Conjugation Using Functionalized Linkers
3.1. Bifunctional Succinyl Linkers
3.2. Redox-Sensitive Disulfide Linkers
3.3. Acid-Sensitive Linkers
4. Conclusions and Future Perspectives
- What functional group within the drug structure is available for coupling to the CPP?It is important to know which groups define the pharmacophore, what positions are useful for modifications, and which reaction conditions are selectable.
- How does the coupled drug influence the CPP?It should be carefully considered which cargo moieties are allowed to be introduced that do not disturb the activity of the CPP.
- Can the tumor/tumor environment be targeted by the chosen linkage strategy?The microenvironment of the tumor tissue is distinguishable to that from healthy cells, and thus, linker systems should be introduced between CPP and drug that enable the generation of a highly active and cell selective anticancer therapeutic.
Funding
Conflicts of Interest
Abbreviations
A2780 | human ovarian carcinoma cells |
ADC | antibody–drug conjugate |
CCRF-CEM | human leukemia carcinoma cells |
CLSM | confocal laser scanning microscopy |
COS7 | primate fibroblast-like kidney cells |
DCM | dichloromethane |
DIC | N,N’-diisopropylcarbodiimide |
DIPEA | N,N’-diisopropylethylamine |
DMA | 2,3-dimethylmaleic anhydride |
DMAP | 4-dimethylaminopyridine |
DMF | dimethylformamide |
DMSO | dimethyl sulfoxide |
EJ | human bladder cancer cells |
GSH | glutathione |
HBTU | hexafluorophosphate benzotriazole tetramethyl uronium |
HEK-293 | human embryonic kidney cells |
HeLa | human cervical cancer cells |
HOBt | hydroxybenzotriazole |
HT-1080 | human fibrosarcoma cells |
HT-29 | human colon cancer cells |
IC50 | half maximal inhibitory concentration |
LLCPK | porcine kidney cells |
MCF-7 | human breast cancer cells |
MDA-MB-231 | epithelial human breast cancer |
MG63 | human osteosarcoma |
MMP-2/9 | metalloproteinase 2 and 9 |
MRP | multidrug resistance protein |
mtDNA | mitochondrial DNA |
NCM460 | normal human colon mucosal epithelial cells |
NHDF | normal human dermal fibroblast cells |
PDC | peptide–drug conjugate |
ROS | reactive oxygen species |
SKOV-3 | human ovarian cancer cells |
TEA | triethylamine |
U87 | human primary glioblastoma |
Wi-38 | normal human fibroblast-like lung cells |
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Name | Sequence | Citation |
---|---|---|
ACPP | RRRRRRRRGGGPKKKKKK | [21] |
Buforin IIb | RAGLQFPVGRLLRRLLRRLLR-NH2 | [22] |
CHAP-1 CHAP-2 CHAP-3 | KR-Aib-IRLFTK-Aib-LK KR-Aib-IRLFTK-Aib-FK KR-Aib-FRLFTK-Aib-FK | [23] |
[C(WR)4K2(β-A)] | RCKβ-ARWRWKWRW | [24] |
[C(WR)4K] | RCRWRWKβ-AWRW | [25] |
H3-V35C | ARTKQTARKSTGGKAPRKQLATKAARKSAPATGGCKK | [26] |
LH | LHHLLHHLHHLLHH | [27] |
LH2 (monomer) | Acetyl-LHHLCHLLHHLCHLAG-NH2 | [28] |
KRP | CSSKEKKKGKKRKKKREREGQKEGGRRKEKRKEKKRKEGGREGRKEGRKSADHPS | [29] |
LMWP | VSRRRRRRGGRRRR | [30] |
MCF-7 targeting CPP | RLYMRYYSPTTRRYG | [31] |
P1 | Kβ-AWRWRWRWRW | [32] |
Penetratin(desMet) | RQIKIWFQNRRKWKK | [33] |
pHLIP | AEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTCG | [34] |
Nucleus targeting CPP | RrRK | [35] |
l-R8 | RRRRRRRR | [33,36] |
d-R8 | rrrrrrrr | [35] |
R9GAL FFFF FFFFR9GAL | RRRRRRRRRGAL FFFF FFFRRRRRRRRRGAL | [37] |
LGA-d-R9C | LGA-rrrrrrrrrC | [38] |
[RW]6 [RW]3 R5W3R3 | RWRWRWRWRWRW RWRWRW RRRRRWWWRRR | [39] |
sC18 | GLRKRLRKFRNKIKEK-NH2 | [40,41,42] |
sC18* | GLRKRLRKFRNK | [43] |
T2 | FKKFFRKLL | [44] |
TAT | CGGGYGRKKRRQRRR | [30,45] |
TH | AGYLLGHINLHHLAHL-Aib-HHIL-NH2 | [46] |
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Gayraud, F.; Klußmann, M.; Neundorf, I. Recent Advances and Trends in Chemical CPP–Drug Conjugation Techniques. Molecules 2021, 26, 1591. https://doi.org/10.3390/molecules26061591
Gayraud F, Klußmann M, Neundorf I. Recent Advances and Trends in Chemical CPP–Drug Conjugation Techniques. Molecules. 2021; 26(6):1591. https://doi.org/10.3390/molecules26061591
Chicago/Turabian StyleGayraud, Félix, Merlin Klußmann, and Ines Neundorf. 2021. "Recent Advances and Trends in Chemical CPP–Drug Conjugation Techniques" Molecules 26, no. 6: 1591. https://doi.org/10.3390/molecules26061591