## 3 Materials and Methods
### Chemistry
#### 3.1.8 General Procedure for the SPPS of Nucleopeptides.  
Nucleopeptides **1, 2** were synthesized manually on resin following the standard Fmoc/tBu solid phase orthogonal protection strategy. Preload Fmoc-Val-Wang resin (0.4 mmol) was swollen DCM/DMF/DCM/DMF (4 \(\times\) 0.5 min), then the resin was treated with a mixture of DBU:piperidine:DMF (I:1:48, in volume) at room temperature (1 \(\times\) 1 min) and (3 \(\times\) 10 min) and washed with DMF/DCM/DMF/DCM (4 \(\times\) 0.5 min). Later, to the free N\(\alpha\)-terminal swollen resin (1 equiv), a solution of the corresponding Fmoc-AA-OH (1.2 equiv.), HCTU (1.2 equiv.) and DIEA (2.4 equiv.) in dry DMF (5 mL) was added.  
The introduction of the first 12 amino acids was carried out under microwave radiation while the introduction of the last three amino acids was carried out at room temperature to prevent the rupture of the phosphate bond.  
1. Coupling procedure of the first 11 amino acids: After sealing the vial, the reaction was heated in a microwave vial equipped with a magnetic stirrer for 10 min at 40 \({}^{\circ}\)C. Then, the vial was opened, the supernatant removed and new coupling mixture added. This process was repeated three times in total (3 \(\times\) 10 min) until complete coupling. Finally, the resin was transferred to a fritted syringe, drained and washed extensively (DMF/DCM/DMF/DCM, 5 \(\times\) 0.5 min). This protocol was repeated for the sequential anchoring of each of the first 12 amino acids.
2. Coupling of the last three amino acids: The mixture was stirred 1 h at room temperature. Then, the vial was opened, the supernatant removed and new coupling mixture added. Finally, the resin was drained and washed extensively (DMF/DCM/DMF/DCM, 5 \(\times\) 0.5 min). This protocol was repeated for the sequential anchoring of each of the last three amino acids of the sequence.  
Coupling reactions to primary amines were monitored by the Kaiser ninhydrin test and to secondary amines by the chloranil test. In some cases, the progress of the reactions was also followed by analysis of a small sample of peptidylresin after acidic cleavage in an HPLC-MS instrument. After elongation of the peptides, the well dried resin-bounded derivative (1 vol) in a fritted syringe was treated with a mixture of TFA:TIPS:water (95:2.5:2.5) (5 vol) for 4 h at room temperature. The filtrates were precipitated over cold Et\({}_{2}\)O and centrifuged three times at 5000 rpm for 10 min. After removing the supernatant, the pellet was redissolved in water/acetonitrile and lyophilized. The crudes were purified by reverse phase chromatography using semipreparative HPLC.  
H-Gly-Pro-Tyr(pFU)-Ala-Gly-Pro-Leu-Glu-Arg-Gln-Arg-Pro-Leu-Lys-Val-OH (**1**)  
The general protocol was followed with 0.039 mmol of resin. After purification of the crude, **1** was isolated as a white lyophilized cotton-like solid (13 mg, 10% overall yield). HPLC (system B): 4.73 min (94% analytical purity). HRMS: [C\({}_{85}\)H\({}_{135}\)FN\({}_{25}\)O\({}_{28}\)P]\({}^{+}\); calcd. 2003.9611, found 2003.9630.  
H-Gly-Pro-Tyr(pU)-Ala-Gly-Pro-Leu-Glu-Arg-Gln-Arg-Pro-Leu-Lys-Val-OH (**2**)  
The general protocol was followed with 0.039 mmol of resin. After purification of the crude, **2** was isolated as a white lyophilized cotton-like solid (14 mg, 18% overall yield). HPLC (system B): 4.43 min (97% analytical purity). HRMS: [C\({}_{85}\)H\({}_{136}\)N\({}_{25}\)O\({}_{28}\)P]\({}^{+}\); calcd. 1985.9746, found. 1985.9724.