Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of Triazolopeptides on Solid Support
2.1.1. Conversion of Primary Amine Group into Azide on Solid Support
2.1.2. Click Reaction on Solid Support
2.1.3. Homoarginine (Har) Synthesis on Solid Support
2.1.4. Final Cleavage from Solid Support and Triazolopeptides Isolation
2.2. Inhibition of NRP-1/VEGF-A
Correlation Analysis
R2 = 0.63, n = 23.
2.3. Molecular Modelling
- -
- Ionic interaction of C-terminal Arg guanidine with Asp320;
- -
- Hydrogen bonds of C-terminal Arg carboxylate with Ser346 and Thr349;
- -
- Dispersive contacts of C-terminal Arg aliphatic portion with the residue lining the binding cleft Tyr353, Tyr 297, Trp301, Thr316, Gly414, Ile415, and Ser416;
- -
- Ionic interaction of Har guanidine with Glu319 or an H-bond of this moiety with carbonyl group of Gly318.
2.4. In Vitro Proteolysis of Triazolopeptides
2.5. In Vitro Cell Survival Test
3. Materials and Methods
3.1. Synthesis
3.1.1. Wong Diazotransfer
3.1.2. Fmoc-Propargylamine (24) Preparation
3.1.3. Click Reaction on Solid Support
3.1.4. Common Procedures for Peptide Chain Elongation on Solid Support
3.1.5. Guanylation Reaction of Lys to Gain Har
3.1.6. Peptidotriazole Cleavage from Solid Support
3.1.7. HPLC Analysis, Purification, and HRMS Characterization
3.2. ELISA Assays of Inhibitory Activity
3.3. Correlation Analysis
3.4. Molecular Dynamics
3.5. Stability
3.6. In Vitro Cell Survival Test
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds 3 and 4 are available from the authors. |
No. | Sequence | RT [min.] | General Formula | Calc. MS [m/z] | Meas. MS [m/z] |
---|---|---|---|---|---|
“linker” subseries | |||||
1 | Lys(Har)-GlyΨ[Trl]Arg | 11.98 1 | C22H43N13O4 | 554.3634 4 | 554.3640 4 |
2 | D-Lys(Har)-GlyΨ[Trl]Arg | 11.96 1 | C22H43N13O4 | 554.3634 4 | 554.3656 4 |
3 | Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 13.22 1 | C25H46N16O4 | 635.3961 4 | 635.3979 4 |
4 | D-Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 13.30 1 | C25H46N16O4 | 635.3961 4 | 635.3980 4 |
5 | D-Lys(D-Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 13.33 1 | C25H46N16O4 | 635.3961 4 | 635.3982 4 |
6 | Lys(Har)-Pro-GlyΨ[Trl]Arg | 14.65 1 | C27H50N14O5 | 651.4161 4 | 651.4187 4 |
7 | D-Lys(Har)-Pro-GlyΨ[Trl]Arg | 14.65 1 | C27H50N14O5 | 651.4161 4 | 651.4190 4 |
8 | Lys(Har)-Phe-GlyΨ[Trl]Arg | 14.89 2 | C31H52N14O5 | 701.4318 4 | 701.4339 4 |
9 | D-Lys(Har)-Phe-GlyΨ[Trl]Arg | 15.04 2 | C31H52N14O5 | 701.4318 4 | 701.4338 4 |
10 | Lys(Har)-GlyΨ[Trl]Ala-Arg | 13.17 1 | C25H48N14O5 | 625.4005 4 | 625.3994 4 |
11 | Lys(Har)-GlyΨ[Trl]Gly-Arg | 12.19 1 | C24H46N14O5 | 611.3848 4 | 611.3878 4 |
12 | Har-Pro-GlyΨ[Trl]Arg | 13.78 1 | C21H38N12O4 | 523.3212 4 | 523.3221 4 |
13 | Har-GlyΨ[Trl]GlyΨ[Trl]GlyΨ[Trl]Arg | 14.52 1 | C22H37N17O3 | 588.3338 4 | 588.3362 4 |
“arm” subseries | |||||
14 | Lys(Fmoc-Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 16.50 3 | C40H56N16O6 | 429.2357 5 | 429.2371 5 |
15 | D-Lys(Fmoc-Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 16.53 3 | C40H56N16O6 | 429.2357 5 | 429.2373 5 |
16 | Har-Lys-GlyΨ[Trl]GlyΨ[Trl]Arg | 13.05 1 | C25H46N16O4 | 635.3961 4 | 635.3991 4 |
17 | Dab(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 12.46 1 | C23H42N16O4 | 607.3648 4 | 607.3675 4 |
18 | Dap(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 11.92 1 | C22H40N16O4 | 593.3491 4 | 593.3517 4 |
19 | Har-6Ahx-GlyΨ[Trl]GlyΨ[Trl]]Arg | 16.83 1 | C25H45N15O4 | 620.3852 4 | 620.3878 4 |
20 | Har-5Ava-GlyΨ[Trl]GlyΨ[Trl]Arg | 15.23 1 | C24H43N15O4 | 606.3695 4 | 606.3721 4 |
21 | Har-Ala-GlyΨ[Trl]GlyΨ[Trl]]Arg | 13.46 1 | C22H39N15O4 | 578.3382 4 | 578.3406 4 |
22 | Har-Gly-GlyΨ[Trl]GlyΨ[Trl]Arg | 13.06 1 | C21H37N15O4 | 564.3226 4 | 564.3244 4 |
23 | Har-GlyΨ[Trl]GlyΨ[Trl]Arg | 13.06 1 | C19H34N14O3 | 507.3020 4 | 507.3011 4 |
No | Sequence | Inhibition of bt-VEGF165 Binding to NRP-1 [10 µM] 1 | IC50 [µM] |
---|---|---|---|
A7R | Ala-Thr-Trp-Lys-Pro-Pro-Arg | 61.0 ± 0.4 3 | 5.86 3 |
KPPR | Lys-Pro-Pro-Arg | 64.5 | 4.60 4 |
Lys(Har)-Dap/Dab-Pro-Arg | 96.8/98.5 | 0.2/0.2 4 | |
“linker” subseries | |||
1 | Lys(Har)-GlyΨ[Trl]Arg | 28.1 ± 1.2 | - |
2 | D-Lys(Har)-GlyΨ[Trl]Arg | 33.1 ± 1.9 | - |
3 | Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 58.1 ± 2.1 | 8.39 2 |
4 | D-Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 52.6 ± 1.3 | 10.22 2 |
5 | D-Lys(D-Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 48.5 ± 2.9 | 9.11 2 |
6 | Lys(Har)-Pro-GlyΨ[Trl]Arg | 18.3 ± 0.9 | - |
7 | D-Lys(Har)-Pro-GlyΨ[Trl]Arg | 38.4 ± 1.5 | - |
8 | Lys(Har)-Phe-GlyΨ[Trl]Arg | 30.9 ± 2.1 | - |
9 | D-Lys(Har)-Phe-GlyΨ[Trl]Arg | 37.9 ± 1.1 | - |
10 | Lys(Har)-GlyΨ[Trl]Ala-Arg | 43.2 ± 1.5 | - |
11 | Lys(Har)-GlyΨ[Trl]Gly-Arg | 30.6 ± 1.1 | - |
12 | Har-Pro-GlyΨ[Trl]Arg | 9.2 ± 0.8 | - |
13 | Har-GlyΨ[Trl]GlyΨ[Trl]GlyΨ[Trl]Arg | 34.8 ± 1.5 | - |
“arm” subseries | |||
14 | Lys(Fmoc-Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 57.7 ± 1.8 | - |
15 | D-Lys(Fmoc-Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 43.7 ± 0.5 | - |
16 | Har-Lys-GlyΨ[Trl]GlyΨ[Trl]Arg | 36.5 ± 1.4 | - |
17 | Dab(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 41.3 ± 0.5 | - |
18 | Dap(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg | 25.3 ± 3.5 | - |
19 | Har-6Ahx-GlyΨ[Trl]GlyΨ[Trl]Arg | 30.5 ± 0.6 | - |
20 | Har-5Ava-GlyΨ[Trl]GlyΨ[Trl]Arg | 29.7 ± 1.8 | - |
21 | Har-Ala-GlyΨ[Trl]GlyΨ[Trl]Arg | 27.8 ± 2.1 | - |
22 | Har-Gly-GlyΨ[Trl]GlyΨ[Trl]Arg | 35.7 ± 1.6 | - |
23 | Har-GlyΨ[Trl]GlyΨ[Trl]Arg | 20.0 ± 2.1 | - |
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Fedorczyk, B.; Lipiński, P.F.J.; Puszko, A.K.; Tymecka, D.; Wilenska, B.; Dudka, W.; Perret, G.Y.; Wieczorek, R.; Misicka, A. Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165. Molecules 2019, 24, 1756. https://doi.org/10.3390/molecules24091756
Fedorczyk B, Lipiński PFJ, Puszko AK, Tymecka D, Wilenska B, Dudka W, Perret GY, Wieczorek R, Misicka A. Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165. Molecules. 2019; 24(9):1756. https://doi.org/10.3390/molecules24091756
Chicago/Turabian StyleFedorczyk, Bartlomiej, Piotr F. J. Lipiński, Anna K. Puszko, Dagmara Tymecka, Beata Wilenska, Wioleta Dudka, Gerard Y. Perret, Rafal Wieczorek, and Aleksandra Misicka. 2019. "Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165" Molecules 24, no. 9: 1756. https://doi.org/10.3390/molecules24091756