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D. .. , Preparation of Cys-Dtph-containing peptides, Preparation of the model linker-containing peptides

. , Native chemical ligation of 8a-c with 16

, Stability study of the linker-containing peptides 8a, 8b and 8c under selected conditions, vol.201

.. .. Study-of-cleavage-kinetics, 202 6. Functionalization of the solid support with thioester 16

. .. Peptides, 209 7.1. Influence of the resin. Synthesis of peptidyl resin 23A-C and Cys-Dtph-containing peptides 24A-C, Synthesis of peptidyl resin 23B, 23D-G and Cys-Dtph-containing peptides 24B

C. .. Avbd2, 230 8.1. Fmoc-SPPS synthesis of AvBD2[1-36] 26F-2, for comparative studies

. , 238 10. Catch-and-release purification of Bv8 peptide, Synthesis of Cys-Dtph-containing peptides, p.251

, Protected amino acids, Rink´s linker, Spheritide TM resin, amino-PEGA resin, HBTU and HCTU were purchased from

, Controlled pore glass beads (TRISOPERL®, pore size: 100 nm, bead diameter: 100-200 ?m, lot number: PG L 14/04 AMINO 225) was obtained from VitraBio

. Biomatrix and . Inc, 10trioxatridecan-succinamic acid (Fmoc-TTDS-OH) and Fmoc-NH-PEG-COOH (3000 Da) were purchased from Iris Biotech GmbH, Fmoc-Ala-methylphenoxypropionic acid (Fmoc-L-Ala-MPAA-OH was obtained from Interchim, vol.7

, All other chemicals were from Sigma Aldrich (St-Quentin-Fallavier, France) and solvents from SDS-Carlo Erba, PyAOP was obtained from aapptec

. Torviq, ) and were equipped with PTFE stopcock bought from Chromoptic

, High resolution ESI-MS analyses were performed on a MaXis TM ultra-high-resolution QTOF mass spectrometer (Bruker Daltonics

, LC/MS analyses were performed on a 6120B single Quadrupole LC/MS system (Agilent Technologies

, HighResolution RP-18e (130 Å, 10 × 4.6 mm, 3 mL/min flow rate) and Jupiter C4 (300 Å, p.5

, × 10 mm, 3 mL/min flow rate)

, 250 × 10 mm, 3 mL/min flow rate) or Jupiter C4 (300 Å, 5 ?m, 250 × 10 and B are 0.1% TFA in H2O and 0.1% TFA in MeCN, respectively. Each gradient was followed by a washing step (up to 95% B/A) to elute any compound not eluted during the gradient. LC/HRMS and LC/MS analyses were carried out respectively on an Ultimate ® 3000 RSLC HPLC system, Hitachi L-2455 diode array detector and a Hitachi L-2200 auto sampler. Nucleosil C18 (300 Å, 5 ?m

, Infinity HPLC system, coupled with the Agilent 6120 mass spectrometer, and fitted with an

, Aeris Widepore XB-C18 2 (3.6 ?m, 150 × 2.1 mm, 0.5 mL/min flow rate, 40°C) column

A. Solvents, 1% formic acid in H2O and 0.08% formic acid in MeCN, respectively. Kiesegel C60 (Merck, Germany) as the stationary phase, and thin layer chromatography analyses were performed on precoated silica gel plates (0.25 mm thick, 60 F254

. Spot-ii-flash, , p.40

, Preparation of the model linker-containing peptides 3.1. Synthesis of Boc-Cys(Trt)-Dtph-Xaa-OH Supplementary figure 1 Synthesis of Boc-Cys(Trt)-Dtph-OH , overall yield 64% Compound 1

, A solution of methyl-6-aminohexanoate hydrochloride (250 mg, 1.6 equiv.) and iPr2EtN (256.2 µL, 1.7 equiv.) in CH2Cl2 (20 mL) was cooled in an ice bath, Then Boc-Cys

, HOBt (0.116 g, 1 equiv.) and DCC (0.213 flash column chromatography (eluent: petroleum ether/ EtOAc, vol.6

H. Nmr, 600 MHz, CDCl3): ? 7.37-7.32 (m, 6H, HTrt), 7.22-7.18 (m, 6H, HTrt), 7.19-7.12 (m, 3H, HTrt), 5.91 (bt, J = 5.9 Hz, 1H, H4), 4.72 (bs, 1H, H1)

2. Hz,

C. Nmr, , vol.174

E. ,

, To a solution of 1 (442 mg, 0.71 mmol, 1 equiv.) in MeOH (16 mL) was added a solution of

, NaOH (120 mg, 4 equiv.) in water (5 mL) and the resulting mixture was heating at 50 °C for 5

H. Nmr, 600 MHz, CDCl3): ? 7.37-7.31 (m, 6H, HTrt), 7.25-7.18 (m, 6H, HTrt), 7.17-7.11 (m, 3H, HTrt), 6.03-5.93 (m, 1H, H4)

2. Hz,

C. Nmr,

E. ,

, A solution of 1,3-dimethylbarbituric acid (115 mg, 1.2 equiv.), compound 2 (355 mg, p.61

, DMAP (90 mg, 1.2 equiv.) in CH2Cl2 (30 mL) were cooled in an ice bath

, EDCI (142 mg, 1.2 equiv.by flash column chromatography (eluent: CH2Cl2/MeOH, vol.99

H. Nmr, 600 MHz, CDCl3): ? 7.48-7.36 (m, 6H, HTrt), 7.35-7.28 (m, 6H, HTrt), 7.26-7.12 (m, 3H, HTrt), vol.6

1. Hz and . H3a,

C. Nmr,

E. , , p.172

, General protocol for the preparation of Boc-Cys(Trt)-Dtph-Xaa-OH: compounds 4a-e A solution of compound 3 (1 equiv.), amino acid (Gly, Ala or Ser(OtBu)

/. Meoh, :2:9) to afford compound 4a-c Compound 4a

H. Nmr, 400 MHz, CDCl3, 55°C): ? 12.89 (s, 1H, H10), 7.36-7.31 (m, 6H, HTrt), 7.22-7.18 (m, 6H, HTrt)

C. Nmr, MHz, issue.150

E. ,

, Boc-Cys(Trt)-Dtph, vol.4

H. Nmr, 400 MHz, CDCl3, 55°C): ? 13.0 (bs, 1H, H10) 7.33-7.31 (m, 6H, HTrt), 7.24-7.19 (m, 6H, HTrt), 7.14-7.11 (m, 3H, HTrt), vol.6

C. Nmr,

E. ,

, Boc-Cys(Trt)-Dtph, vol.4

H. Nmr, 400 MHz, CDCl3, 55°C): ? 12.91 (m, 1H, H10), 7.44-7.26 (m, 6H, HTrt), 7.24-7.16 (m, 6H, HTrt), 7.16-7.05 (m, 3H, HTrt), vol.6, pp.33-39

. Hz,

C. Nmr, MHz, issue.150

E. ,

, Boc-Cys(Trt)-Dtph, vol.4

H. Nmr, 400 MHz, CDCl3, 55°C): ? 7.48-7.34 (m, 6H, HTrt), 7.33-7.26 (m, 6H, HTrt), 7.267.17 (m, 3H, HTrt), vol.12, pp.167-168

C. Nmr, MHz, issue.150

E. ,

, Boc-Cys(Trt)-Dtph-Ser, vol.4

H. Nmr, 400 MHz, CDCl3, 55°C): ? 7.47-7.36 (m, 6H, HTrt), 7.34-7.26 (m, 6H, HTrt), 7.267.16 (m, 3H, HTrt), 6.22 (bt, J = 5.7 Hz, 1H, H4), vol.5, pp.23-513

C. Nmr, MHz, CDCl3): ? 176, vol.9

E. ,

E. Calcd,

, HPLC purification: retention time: 8.05 min (Nucleosil

, ESI-HRMS (m/z): [M+H] + calcd. for C106H160N32O32S: 2426.1597, found: 2426.1666. HPLC analysis: retention time: 2.88 min

, HPLC purification: retention time: 2.1min (Nucleosil, gradient: 24-36 % B/A over 20 min, vol.9

, HPLC analysis: retention time: 2.88 min (Chromolith, gradient: 20-50 % B/A over 5 min), ESI-HRMS (m/z): [M+H] + calcd. for C107H162N32O32S: 2440.1754

, HPLC purification: retention time: 14.29 min (Nucleosil, gradient: 24-36 % B/A over 20 min, 11: ESI-HRMS mass spectrum of 6c

, Supplementary figure 12: Synthesis of 14

, Benzyl mercaptan (2.6 mL, 22 mmol, 1.1 equiv.) was added under argon to a stirred solution of succinic anhydride (2.0 g, 20 mmol, 1 equiv.) and 4-(dimethylamino)-pyridine (122 mg, p.1

D. A. Stetsenko and M. J. Gait, J Org Chem, vol.65, p.4900, 2000.

, M HCl solution, followed by ice-cold water, and then dissolved in powder (854 mg, 19%)

H. Nmr, 600 MHz, DMSO-d6): ? 12.28 (s, 1H, H1), 7.37-7.17 (m, 5H, HAr

, Supplementary figure 13: synthesis of 16, overall yield 40%

G. J. Bernardes, E. J. Grayson, S. Thompson, J. M. Chalker, J. C. Errey et al., Angew. Chem. Int. Ed. Engl, vol.47, issue.12, p.37, 2008.