Template for Communications for the Journal of the American Chemical Society

Supplementary Information

Cyclic RGD peptides interfere with binding of the Helicobacter pylori protein CagL to integrins V3

and 51.

Jens Conradi, Sylwia Huber (née Urman)&, Katharina Gaus≠, Felix Mertink, Soledad Royo Gracia‡, Ulf Strijowski#, Steffen Backert, Norbert Sewald* ()

J. Conradi, S. Huber (née Urman)&, K. Gaus≠, F. Mertink, S. Royo Gracia‡, U. Strijowski#, N. Sewald Department of Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany E-mail: [email protected]

S. Backert School of Biomolecular and Biomedical Sciences, University College Dublin, Ardmore House, Belfield Campus, Dublin-4, Ireland

≠ Present address: Syngenta, Schaffhauserstrasse, 4332 Stein, Switzerland & Present address: F. Hoffmann – La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland # Present address: German Institute of Food Technologies, Professor-von-Klitzing-Straße 7, 49610 Quakenbrück, Germany ‡ Present address: Institute for Research in Biomedicine, Baldiri Reixac 10, 08028 Barcelona, Spain

*Corresponding author: Prof. Dr. Norbert Sewald Bielefeld University Department of Chemistry PO Box 10 01 31 D-33501 Bielefeld Tel. int.: +49-(0)521-106 2051 Fax int.: +49-(0)521-106 8094 E-mail: [email protected]

1 Table S1. NMR experiments, acquisition and processing parameters. Experiment Pulse Program TD NS Other Processing Parameters 1H Zg 32-64 K 32-64 32K, exp., LB 0.3 1H zg30 32K 32 T=295, 300, 305, 310, 315, 325 K, 120K, exp., LB 0.3 COSY cosydfph 2K X 512 16 2K X 2K, sin2, +/2

COSY cosydfph 2K X 256 16 T=295, 300, 305, 310, 315, 325 K, 2K X 2K, sin2, +/2

TOCSY Dipsi2ph 2K X 256 16 τm=80 ms 2 2K X 512 2K X 2K, sin , +/2

ROESY roesyph 2K X 256 16 τm=200 ms 2K X 512 2K X 2K, sin2, +/2

NOESY noesyph 4K X 512 16 τm=200,250, 300, 350, 400, 450 ms 2K X 2K, sin2, +/2 1 13 H, C-HSQC hsqcetgpsisp2 2K X 256 32-64 JC,H=145 Hz hsqcedetgpsisp 2K X 512 2K X 2K, sin2, +/2

HMBC hmbcgpndqf 4K X 512 32-48 JC,H=145 Hz hmbclpndqf 2-4K X 1K, sin2 or sin 1 15 H, N-HSQC hsqcetf3gpsi 2Kx256 64-256 JN,H=90 Hz 2Kx512 2K X 256, sin2, +/2 13C zgpg30 64K 10-32K 32K, exp., LB 1.0 DEPT-135 dept135 64K 10K 32K, exp., LB 1.0

TD: time domain; NS: number of scans; SW: sweep width; O1P: transmitter frequency

Figure S1. Structural analysis of peptides, workflow overview (MD: molecular dynamics, DG: distance geometry, SA: simulated annealing) (Gaus 2009).

2 Figure S2. Sigmoidal dose-response plots of the competitive cell adhesion assays for cyclic peptides 1-7 inhibiting the binding of WM-115 cells to the CagLWT, CagLRAD and CagLRGA proteins.

3 Table S2. Distances derived from NOESY correlations of c-(-Arg-Gly-Asp-D-Leu-Ala-) 2 in DMSO-D6, d: distance, exp: experimental value, rMD: average value adopted over all trajectories in restrained molecular dynamics calculations, fMD: average value obtained by the combined trajectories in unrestrained molecular dynamics calculations. d / pm Atom 1 Atom 2 Exp Tolerance rMD fMD Arg-1 Hα Arg-1 HN 285 ±28 281 284 Arg-1 Qβ D-Leu-4 HN 361 ±36 569 735 Arg-1 Qβ Arg-1 Hα 327 ±33 256 253 Arg-1 Qβ Arg-1 Qδ 404 ±40 274 277 Arg-1 Qβ Arg-1 HN 408 ±41 274 276 Arg-1 Qβ Gly-2 HN 381 ±38 267 344 Arg-1 Qδ Arg-1 Hα 415 ±41 330 304 Arg-1 Qγ Arg-1 Hα 349 ±35 263 270 Arg-1 Qγ Arg-1 Qβ 259 ±26 233 231 Gly-2 Qα Asp-3 HN 371 ±37 287 280 Gly-2 Qα Asp-3 HN 316 ±32 287 280 Asp-3 Hα Asp-3 HN 330 ±33 282 284 Asp-3 Hα D-Leu-4 HN 264 ±26 251 221 Asp-3 Qβ Asp-3 Hα 333 ±33 255 247 Asp-3 Qβ Asp-3 HN 361 ±36 267 270 D-Leu-4 Hα D-Leu-4 HN 344 ±34 277 282 D-Leu-4 Hα Ala-5 HN 226 ±23 223 220 D-Leu-4 Qβ D-Leu-4 HN 375 ±37 301 273 D-Leu-4 Qβ D-Leu-4 Hα 313 ±31 255 255 D-Leu-4 Qβ Ala-5 HN 432 ±43 370 406 Ala-5 Hα Ala-5 HN 327 ±33 266 278 Ala-5 Mβ Ala-5 Hα 322 ±32 242 241 Ala-5 Mβ Ala-5 HN 271 ±27 273 280

Table S3. Distances derived from NOESY correlations of c-(-Arg-Gly-Asp-Leu-D-Ala-) 3 in DMSO-D6, d: distance, exp: experimental value, rMD: average value adopted over all trajectories in restrained molecular dynamics calculations, fMD: average value obtained by the combined trajectories in unrestrained molecular dynamics calculations. d / pm Atom 1 Atom 2 Exp Tolerance rMD fMD Arg-1 Hα Arg-1 HN 233 ±23 276 280 Arg-1 Hα Gly-2 HN 268 ±27 220 224 Arg-1 Qβ Arg-1 Hα 281 ±28 252 252 Arg-1 Qβ Arg-1 Qδ 342 ±34 271 275 Arg-1 Qβ Arg-1 Hε 422 ±42 330 333 Arg-1 Qβ Arg-1 HN 334 ±33 274 270 Arg-1 Qβ Gly-2 HN 375 ±37 374 366 Arg-1 Qδ Arg-1 Hα 352 ±35 382 325 Arg-1 Qδ Arg-1 Hε 356 ±36 185 185 Arg-1 Qδ Arg-1 HN 453 ±45 437 456 Gly-2 Qα Leu-4 HN 365 ±36 491 483 Asp-3 Qβ Gly-2 Qα 438 ±44 521 516 Asp-3 Qβ Asp-3 HN 251 ±25 281 271 Asp-3 Qβ Leu-4 HN 303 ±30 271 275 Leu-4 Hα Leu-4 HN 281 ±28 284 285 Leu-4 Qβ Asp-3 Qβ 527 ±53 480 468 Leu-4 Qβ Leu-4 Hα 240 ±24 253 254 Leu-4 Qβ Leu-4 HN 304 ±30 277 276 Leu-4 Qβ D-Ala-5 HN 358 ±36 404 407 Leu-4 Qδ Leu-4 Hα 423 ±42 331 342 Leu-4 Hγ Leu-4 HN 356 ±36 310 330 Leu-4 Hγ D-Ala-5 HN 545 ±55 420 389 D-Ala-5 Mβ Arg-1 HN 386 ±39 396 407 D-Ala-5 Mβ D-Ala-5 HN 260 ±26 276 277

4 Table S4. Distances derived from NOESY correlations of c-(-Arg-Gly-Asp-D-Leu-Ala-Leu-) 4 in DMSO-D6, d: distance, exp: experimental value, rMD: average value adopted over all trajectories in restrained molecular dynamics calculations, fMD: average value obtained by the combined trajectories in unrestrained molecular dynamics calculations. d / pm Atom 1 Atom 2 Exp Tolerance rMD fMD Arg-1 Hα Asp-3 HN 331 ±33 378 443 Arg-1 Qβ Arg-1 Hα 239 ±24 257 253 Arg-1 Qβ Arg-1 Qδ 259 ±26 270 274 Arg-1 Qβ Arg-1 Hε 375 ±37 347 344 Arg-1 Qδ Arg-1 Hα 374 ±37 335 310 Arg-1 Qδ Arg-1 HN 449 ±45 407 430 Arg-1 Qδ Gly-2 HN 444 ±44 437 457 Arg-1 Qγ Arg-1 Qδ 305 ±31 234 234 Arg-1 Qγ Arg-1 Hε 431 ±43 261 259 Arg-1 Qγ Arg-1 Hα 344 ±34 263 267 Gly-2 Qα Asp-3 HN 297 ±30 305 281 Asp-3 Hα Gly-2 HN 466 ±47 463 477 Asp-3 Hα Asp-3 HN 297 ±30 277 276 Asp-3 Hα D-Leu-4 HN 254 ±25 218 218 Asp-3 Hβ2 Gly-2 HN 607 ±61 549 537 Asp-3 Hβ2 Asp-3 HN 298 ±30 291 257 Asp-3 Hβ2 D-Leu-4 HN 546 ±55 431 393 Asp-3 Hβ3 Asp-3 HN 343 ±34 306 304 Asp-3 Hβ3 D-Leu-4 HN 527 ±53 378 331 D-Leu-4 Hα D-Leu-4 HN 308 ±31 271 275 D-Leu-4 Qβ D-Leu-4 Hα 289 ±29 255 256 D-Leu-4 Qβ D-Leu-4 HN 267 ±27 269 262 D-Leu-4 Qδ D-Leu-4 Hα 421 ±42 346 336 D-Leu-4 Hγ D-Leu-4 HN 334 ±33 251 272 Ala-5 Mβ Ala-5 HN 284 ±28 274 279 Ala-5 Mβ Leu-6 HN 356 ±36 349 331 Leu-6 Hα Leu-6 Qδ 328 ±33 336 347 Leu-6 Hα Arg-1 HN 256 ±26 233 235 Leu-6 Hα Leu-6 HN 302 ±30 243 253 Leu-6 Qβ Asp-3 HN 449 ±45 432 462 Leu-6 Qβ Leu-6 Hα 287 ±29 255 254 Leu-6 Qβ Leu-6 HN 364 ±36 289 281 Leu-6 Qδ Leu-6 Qβ 377 ±38 260 259

5 Table S5. Distances derived from NOESY correlations of c-(-Arg-Gly-Asp-Leu-D-Ala-Leu-) 5 in DMSO-D6, d: distance, exp: experimental value, rMD: average value adopted over all trajectories in restrained molecular dynamics calculations, fMD: average value obtained by the combined trajectories in unrestrained molecular dynamics calculations. d / pm Atom 1 Atom 2 Exp Tolerance rMD fMD Arg-1 Hα Gly-2 HN 243 ±24 216 219 Arg-1 Hα Asp-3 HN 439 ±44 493 533 Arg-1 Hα Leu-6 HN 508 ±51 489 484 Arg-1 Qβ Arg-1 Hα 243 ±24 255 250 Arg-1 Qβ Arg-1 Qδ 339 ±34 272 273 Arg-1 Qβ Arg-1 Hε 424 ±42 350 343 Arg-1 Qβ Arg-1 HN 318 ±32 290 278 Arg-1 Qβ Gly-2 HN 374 ±37 347 344 Arg-1 Qδ Arg-1 Hα 348 ±35 316 321 Arg-1 Qδ Arg-1 Hε 312 ±31 185 185 Arg-1 Qδ Arg-1 HN 490 ±49 467 450 Arg-1 Qδ Gly-2 HN 548 ±55 424 434 Arg-1 Qγ Arg-1 Hα 242 ±24 267 271 Arg-1 Qγ Arg-1 Qδ 278 ±28 234 234 Arg-1 Qγ Arg-1 Hε 369 ±37 260 260 Arg-1 Qγ Arg-1 HN 319 ±32 337 317 Arg-1 Qγ Gly-2 HN 380 ±38 391 378 Gly-2 Qα Gly-2 HN 248 ±25 236 237 Gly-2 Qα Arg-1 Hα 425 ±42 420 424 Gly-2 Qα Asp-3 Hα 442 ±44 435 429 Gly-2 Qα Asp-3 HN 213 ±21 275 268 Asp-3 Hβ3 Asp-3 HN 320 ±32 282 292 Asp-3 Hβ3 Leu-4 HN 406 ±41 276 293 Leu-4 Hα D-Ala-5 HN 213 ±21 215 219 Leu-4 Qδ Leu-4 Hα 408 ±41 345 345 D-Ala-5 Hα Arg-1 HN 329 ±33 371 383 D-Ala-5 Hα D-Ala-5 HN 310 ±31 276 274 D-Ala-5 Hα Leu-6 HN 206 ±21 211 212 D-Ala-5 Mβ Leu-4 Hα 531 ±53 472 481 DAla-5 Mβ DAla-5 Hα 274 ±27 241 241 DAla-5 Mβ DAla-5 HN 282 ±28 284 272 DAla-5 Mβ Leu-6 Hα 564 ±56 491 493 DAla-5 Mβ Leu-6 HN 349 ±35 376 384 Leu-6 Hα Arg-1 HN 301 ±30 301 305 Leu-6 Hα Leu-6 HN 310 ±31 277 279 Leu-6 Qδ Leu-6 Hα 299 ±30 341 348

6 Table S6. Distances derived from NOESY correlations of c-(-Arg-Gly-Asp-Leu-Ala-D-Leu-) 6 in DMSO-D6, d: distance, exp: experimental value, rMD: average value adopted over all trajectories in restrained molecular dynamics calculations, fMD: average value obtained by the combined trajectories in unrestrained molecular dynamics calculations. d / pm Atom 1 Atom 2 Exp Tolerance rMD fMD Arg-1 Hα Arg-1 HN 319 ±32 279 280 Arg-1 Hα Gly-2 HN 304 ±30 253 232 Arg-1 Qβ Arg-1 Hα 284 ±28 247 252 Arg-1 Qβ Arg-1 Qδ 382 ±38 271 272 Arg-1 Qβ Arg-1 Hε 452 ±45 340 346 Arg-1 Qβ Arg-1 HN 393 ±39 279 280 Arg-1 Qδ Arg-1 Hα 388 ±39 333 318 Arg-1 Qδ Arg-1 Hε 283 ±28 185 185 Gly-2 Qα Gly-2 HN 277 ±28 251 247 Gly-2 Qα Asp-3 HN 433 ±43 252 260 Gly-2 Qα Leu-4 HN 423 ±42 440 447 Gly-2 Qα Ala-5 HN 327 ±33 483 526 Asp-3 Hα Asp-3 HN 358 ±36 256 271 Asp-3 Hα Leu-4 HN 189 ±19 342 340 Asp-3 Qβ Asp-3 Hα 281 ±28 232 248 Asp-3 Qβ Asp-3 HN 336 ±34 285 275 Asp-3 Qβ Leu-4 HN 311 ±31 306 299 Leu-4 Hα Leu-4 HN 398 ±40 280 280 Leu-4 Hβ2 Leu-4 Hα 315 ±32 272 272 Leu-4 Hβ2 Leu-4 HN 346 ±35 242 242 Leu-4 Hβ2 Ala-5 HN 324 ±32 278 289 Leu-4 Hβ3 Leu-4 HN 394 ±39 300 309 Leu-4 Hβ3 Ala-5 HN 294 ±29 297 272 Leu-4 Qδ Leu-4 Hα 326 ±33 349 337 Leu-4 Hγ Leu-4 HN 307 ±31 285 288 Ala-5 Hα Ala-5 HN 264 ±26 275 263 Ala-5 Mβ Ala-5 Hα 240 ±24 242 242 Ala-5 Mβ Ala-5 HN 308 ±31 303 294 Ala-5 Mβ D-Leu-6 HN 349 ±35 358 369 D-Leu-6 Hα Arg-1 HN 234 ±23 213 218 D-Leu-6 Hα Gly-2 HN 404 ±40 395 437 D-Leu-6 Hα D-Leu-6 HN 325 ±33 272 275 D-Leu-6 Qβ D-Leu-6 Hα 290 ±29 256 256 D-Leu-6 Qβ D-Leu-6 HN 311 ±31 258 264 D-Leu-6 Qδ Arg-1 HN 461 ±46 467 505 D-Leu-6 Qδ D-Leu-6 Hα 356 ±36 323 345

7 Table S7. Distances derived from ROESY correlations of c-(-Arg-Ala-Asp-D-Leu-Ala) 7 in DMSO-D6, d: distance, exp: experimental value, rMD: average value adopted over all trajectories in restrained molecular dynamics calculations, fMD: average value obtained by the combined trajectories in unrestrained molecular dynamics calculations. d / pm Atom 1 Atom 2 Exp Tolerance rMD fMD Arg-1 Hα Arg-1 Qβ 247 ±25 378 443 Arg-1 Hα Arg-1 Qγ 320 ±32 257 253 Arg-1 Hα Arg-1 Qδ 279 ±28 270 274 Arg-1 HN Arg-1 Hα 224 ±22 347 344 Arg-1 HN Arg-1 Qβ 332 ±33 335 310 Arg-1 HN Ala-5 Mβ 340 ±34 407 430 Ala-2 HN Arg-1 Qβ 271 ±27 437 457 Ala-2 HN Arg-1 HN 262 ±26 234 234 Ala-2 HN Ala-2 Hα 240 ±24 261 259 Ala-2 HN Ala-2 Mβ 365 ±36 263 267 Asp-3 Hα Asp-3 Qβ 219 ±22 305 281 Asp-3 HN Ala-2 Hα 267 ±27 463 477 Asp-3 HN Ala-2 Mβ 377 ±38 277 276 Asp-3 HN Asp-3 Hα 206 ±21 218 218 Asp-3 HN Asp-3 Qβ 288 ±29 549 537 D-Leu-4 Hα D-Leu-4 Qβ 225 ±23 291 257 D-Leu-4 Hα D-Leu-4 Qδ 272 ±27 431 393 D-Leu-4 Hα D-Leu-4 Hγ 333 ±33 306 304 D-Leu-4 Qβ D-Leu-4 Qδ 270 ±27 378 331 D-Leu-4 HN D-Leu-4 Hα 238 ±24 271 275 D-Leu-4 HN D-Leu-4 Qβ 323 ±32 255 256 D-Leu-4 HN D-Leu-4 Hγ 384 ±38 269 262 Ala-5 HN Arg-1 HN 270 ±27 346 336 Ala-5 HN D-Leu-4 Hα 212 ±21 251 272 Ala-5 HN Ala-5 Hα 240 ±24 274 279 Ala-5 HN Ala-5 Mβ 297 ±30 349 331

Table S8. Comparison of coupling constants JHNHα calculated by Karplus equation from the torsion angles observed in the structure proposal (calc.) to experimentally obtained torsion angles (exp.), secondary structure elements (and the position of the respective amino acid therein), hydrogen bonding observed during the trajectory (population > 5 %) and temperature gradients of the chemical shift of the amide protons Δδ/ΔT in ppb/K for c-(-Arg-Gly-Asp-D-Leu-Ala-) 2.

JHNHα Secondary Amino Structure Hydrogen Δδ/ΔT Acid calc. exp. Element bonding [ppb/K] βII’ (i+3) Arg-1 9.7 n.o. γ (i) -1.7 Gly-2 5.6/7.9 3.9/7.9 γ (i+1) -3.9 γ (i+2) Asp-3 HN - βII’ (i) Asp-3 9.5 7.9 Arg-1 O -3.4 (15 %) D-Leu-4 9.7 8.5 βII’ (i+1) -3.3 Ala-5 8.8 6.9 βII’ (i+2) -3.7

Table S9. Comparison of coupling constants JHNHα calculated by Karplus equation from the torsion angles observed in the structure proposal (calc.) to experimentally obtained torsion angles (exp.), secondary structure elements (and the position of the respective amino acid therein), hydrogen bonding observed during the trajectory (population) and temperature gradients of the chemical shift of the amide protons Δδ/ΔT in ppb/K for c-(-Arg-Gly-Asp-Leu-D-Ala-) 3.

JHNHα Secondary Amino Structure Hydrogen Δδ/ΔT Acid calc. exp. Element bonding [ppb/K] γ (i+2) Arg-1 HN - γ (i) Arg-1 9.2 8.7 βII’ (i) Leu-4 O -5.3 γi (i+1) (10 %) γ (i+1) Gly-2 3.4/9.6 4.7/6.7 βII’ (i+1) -2.6 γi (i) γ (i+2) Asp-3 9.4 7.1 βII’ (i+2) -5.5 βII’ (i+3) Leu-4 9.7 8.0 γ (i) 0.1 D-Ala-5 8.9 7.1 γ (i+1) -6.5 8 γi (i+2)

Table S10. Comparison of coupling constants JHNHα calculated by Karplus equation from the torsion angles observed in the structure proposal (calc.) to experimentally obtained torsion angles (exp.), secondary structure elements (and the position of the respective amino acid therein), hydrogen bonding observed during the trajectory (population) and temperature gradients of the chemical shift of the amide protons Δδ/ΔT in ppb/K for c-(-Arg-Gly-Asp- D-Leu-Ala-Leu-) 4.

JHNHα Secondary Amino Structure Hydrogen Δδ/ΔT Acid calc. exp. Element bonding [ppb/K] Arg-1 3.2 3.7 βII (i+1) -5.9 Gly-2 2.6/9.7 5.0/7.2 βII (i+2) -9.8 βII (i+3) Asp-3 HN - βII’ (i) Asp-3 9.1 6.9 Leu-6 O -2.1 (29 %) D-Leu-4 5.2 4.9 βII’ (i+1) -8.1 Ala-5 7.9 7.9 βII’ (i+2) -8.5 βII’ (i+3) Leu-6 HN - βII (i) Leu-6 8.3 9.2 Asp-3 O -1.0 (23%)

Table S11. Comparison of coupling constants JHNHα calculated by Karplus equation from the torsion angles observed in the structure proposal (calc.) to experimentally obtained torsion angles (exp.), secondary structure elements (and the position of the respective amino acid therein), hydrogen bonding observed during the trajectory (population) and temperature gradients of the chemical shift of the amide protons Δδ/ΔT in ppb/K for c-(-Arg-Gly-Asp-Leu- D-Ala-Leu-) 5.

JHNHα Secondary Amino Structure Hydrogen Δδ/ΔT Acid calc. exp. Element bonding [ppb/K] Arg-1 βII’ (i+3) Arg-1 HN - βII’ (i) 9.6 7.3 Leu-4 O -2.7 (19 %) Gly-2 6.5/6.7 4.8/5.7 βII‘ (i+1) -5.9 Asp-3 9.6 7.7 βII’ (i+2) -4.3 Leu-4 βII’ (i+3) Leu-4 HN - βII’ (i) 9.4 8.0 Arg-1 O -1.1 (16 %) D-Ala-5 6.1 6.2 βII’ (i+1) -7.6 Leu-6 8.9 7.6 βII’ (i+2) -6.7

Table S12. Comparison of coupling constants JHNHα calculated by Karplus equation from the torsion angles observed in the structure proposal (calc.) to experimentally obtained torsion angles (exp.), secondary structure elements (and the position of the respective amino acid therein), hydrogen bonding observed during the trajectory (population) and temperature gradients of the chemical shift of the amide protons Δδ/ΔT in ppb/K for c-(-Arg-Gly-Asp-Leu-Ala- D-Leu-) 6.

JHNHα Secondary Amino Structure Hydrogen Δδ/ΔT Acid calc. exp. Element bonding [ppb/K] Arg-1 Arg-1 HN - 9.7 9.5 βII’ (i+2) Leu-4 O -6.8 (10 %, 2nd Cluster) Gly-2 Gly-2 HN - 4.1/4.6 8.7/3.4 βII’ (i+3) Ala-5 O -1.6 βI (i) (13 %) Asp-3 9.6 5.9 βI (i+1) -5.4 Leu-4 Leu-4 HN - 9.5 9.4 βI (i+2) Arg-1 O -4.2 (9 %) Ala-5 βI (i+3) 9.3 6.5 βII’ (i) -0.3 D-Leu-6 6.2 5.2 βII’ (i+1) -6.7

9 Figure S13. Analytical RP-HPLC chromatogram of c-(-Arg-Gly-Asp-D-Phe-Val-) 1.

Figure S14. Analytical RP-HPLC chromatogram of c-(-Arg-Gly-Asp-D-Leu-Ala-) 2.

Figure S15. Analytical RP-HPLC chromatogram of c-(-Arg-Gly-Asp-Leu-D-Ala-) 3.

10 Figure S16. Analytical RP-HPLC chromatogram of c-(-Arg-Gly-Asp-D-Leu-Ala-Leu-) 4.

Figure S17. Analytical RP-HPLC chromatogram of c-(-Arg-Gly-Asp-Leu-D-Ala-Leu-) 5.

Figure S18. Analytical RP-HPLC chromatogram of c-(-Arg-Gly-Asp-Leu-Ala-D-Leu-) 6.

11 Figure S19. Analytical RP-HPLC chromatogram of c-(-Arg-Ala-Asp-D-Leu-Ala-) 7.