1

Table S1. Data collection and refinement statistics

Space group Cell parameters, Å Complex/a.u. Resolution a, Å Number of reflections Total Unique Rmerge

b, % Completeness, % Redundancy I/σ, (I)

P21 a=33.57, b=46.50, c=49.35

2 50-1.93 (1.96-1.93)

19,068 11, 041

0.11 (0.47) 95.0 (90.3) 3.0 (2.8) 10.7 (2.0)

Resolution, Å Rc, % Rfree

d, % No. of protein atoms No. of D-peptide atoms No. of water molecules Root mean square deviation Bond lengths, Å Bond angles, ° Ramachandran plot Most favored region, % Additional allowed region, % Generously allowed region, % Disallowed region, %

20-1.93 20.9 25.8 1597 218 106

0.020 1.70

90.5 9.5 0.0 0.0

aAll data (outer shell). bRmerge = ∑│I - <I>│/∑I, where I is the observed intensity and <I> is the average intensity obtained from multiple observations of symmetry-related reflections after rejections cR = ∑║Fo│- │ Fc║/∑│Fo │, where Fo and Fc are the observed and calculated structure factors, respectively dRfree = defined by Brünger (1)

2

1. Peptide and protein synthesis and characterization. All peptides and proteins used in this work were chemically synthesized, either in a stepwise fashion or via native chemical ligation, using a machine-assisted Boc chemistry tailored from the optimized HBTU activation/DIEA in situ neutralization protocol originally developed by Kent and colleagues (2). MBHA resin was used for the synthesis of D-peptides/proteins, whereas L-peptides/proteins were made on –OCH2Pam-resins. The synthesis of 25-109MDM2, 24-108MDMX and N79K-biotin-L25-109MDM2 was described previously (3, 4). Identical procedures were used for the preparation of N79K-biotin-D-25-109MDM2 composed entirely of D-amino acids and Gly. All peptides/proteins were purified to homogeneity by reversed-phase HPLC, and their molecular masses ascertained by electrospray ionization mass spectrometry. The biotinylated D-polypeptide was dissolved at 1 mg/ml in 6 M GuHCl, followed by a 6-fold dilution with PBS containing 0.5 mM TCEP and an extensive dialysis (MWCO 3500) against the same buffer. The determined molecular mass of 10383.1 ± 0.5 Da is in agreement with the expected values of 10383.4 Da calculated on the basis of the average isotopic compositions of the folded D-protein (Figure S1). To demonstrate the correct folding of N79K-biotin-D-25-

109MDM2, we quantified the direct interaction of the D-protein with the D-enantiomer of 15-29p53 using the surface plasmon resonance (SPR) technique. As a control, N79K-biotin-L-25-109MDM2 binding to immobilized L-15-29p53 was also measured. Non-linear regression analyses of the steady-state binding kinetics yielded Kd values of 216 and 300 nM, respectively, for the D-protein/D-peptide and L-protein/L-peptide pairs (Figures S2), confirming that the D- and L-enantiomers of 25-109MDM2 function equivalently in their own respective chiral space. Figure S1. Synthetic N79K-biotin-D-25-109MDM2 analyzed by HPLC and ESI-MS. RP-HPLC analysis was performed at 40 °C on a Waters XBridgeTM C18 column (3.5 µm, 4.6 x 150 mm) using a linear gradient of 5-65% acetonitrile containing 0.1% TFA at a flow rate of 1 ml/min over 30 min.

3

Figure S2. Steady-state binding of biotin-LMDM2 to immobilized L-(15-29)p53 (150 RU, left panel) and of biotin-DMDM2 to immobilized D-(15-29)p53 (120 RU, right panel) was quantified by SPR, and the fitted curves (insets) are the mean of two independent experiments (error bars too small to be seen). 2. Mirror image phage display. Ph.D.-12TM - a combinatorial library of random peptide 12-mers fused, via a short spacer GlyGlyGlySer, to the N-terminus of a minor coat protein (pIII) of M13 phage – was purchased from New England Biolabs, Inc. The basic procedures for library screening are as follows: (1) incubate input phage (10 µl) with 400 µl of 100 nM N79K-biotin-D-25-109MDM2 for 30 min at room temperature before adding the phage-target solution to 50 µl streptavidin-agarose resin (Thermo Scientific) for affinity capturing; (2) add 4 µl of 10 mM biotin and incubate, and wash unbound phage; (3) elute bound phage with 400 µl of 1 mM D-15-

29p53; (4) amplify the eluate in E. coli ER2738 and purify phage for next round of panning; (5) repeat steps 1-4; (6) sequence randomly selected binding clones according to the procedures recommended by the manufacturer.

biotinylated LMDM2-Lp53(15-29)

Kd = 300 ± 28 nM

biotinylated DMDM2-Dp53(15-29)

Kd = 216 ± 4 nM

D W W P L A F E A L L R

D W W P L A F E A L L R

D W W P L A F E A L L R

D W W P L A F E A L L R

D W W P L A F E A L L R

D W W P L A F E A L L R

D W W P L A F E A L L R

V R P W Y T E F Q N L L

F D L H K N N D G S R E

I P G H L R D S H T V A

D W W P L A F E A L L R

D W W P L A F E A L L R

D W W P L A F E A L L R

D W W P L A F E A L L R

D W W P L A F E A L L R

Y P A P Q T E R T P L T

M Q A N L A P P L A G D

A H R H P I S F L S T L

H S T T R E F L S S L M

N L N H P T R Y W D P P

4

Figure S3. Amino acid sequences of 20 MDM2-binding clones after four rounds of selection. The sequences in the top panel and those in the bottom panel were obtained separately from two independent phage display experiments. Only the 12 identical sequences are highlighted in bold. Of note, VRPWYTEFQNLL also competitively bound to MDM2 with a Kd value of 118 nM, while the remaining 7 peptides showed little or no binding presumably due to the lack of properly positioned hydrophobic residues in their sequences. An unusually low sequence diversity of the productive binders resulted at least in part from a high-stringency selection using a single low concentration (100 nM) of MDM2. 3. Surface plasmon resonance (SPR). Competition binding kinetics was carried out at 20 °C using a Biacore T100 SPR instrument and 15-29p53-immobilized CM5 sensor chips as described (3, 5, 6). 50 nM 25-109MDM2 or 100 nM 24-108MDMX was incubated in 10 mM HEPES buffer containing 150 mM NaCl, 0.005% surfactant P20, pH 7.4, with varying concentrations of peptide inhibitor before SPR analysis. The concentration of unbound MDM2 or MDMX in solution was deduced, based on p53-association RU values, from a calibration curve established by RU measurements of different concentrations of MDM2/MDMX injected alone. Protein and peptide solutions were quantified by UV absorbance measurements at 280 nm using molar extinction coefficients calculated from a published algorithm (7). Figure S4. Quantification of the interaction of 25-109MDM2 and 24-108MDMX with PMI and DPMI-γ by an SPR-based competition binding assay at 25 °C. 25-109MDM2 (50 nM) or 24-

108MDMX (100 nM) was incubated for 30 min with peptide varying two-fold from 400 to 0.39 nM (25.6 µM to 25 nM for DPMI-γ-MDMX) in 10 mM HEPES, 150 mM NaCl, 0.005% surfactant P20, pH 7.4, and analyzed on a 15-29p53-immobilized CM5 sensor chip. Non-linear regression analysis was performed using GraphPad Prism 4 to give rise to Kd values using the equation Kd = [peptide][MDM2/MDMX]/[complex]. Each curve is the mean of three independent measurements.

Kd (PMI-MDM2)

3.2 ± 1.1 nM

Kd (PMI-MDMX)

8.5 ± 1.7 nM

Kd (DPMI-MDMX)

4.9 ± 0.1 µM

Kd (DPMI-MDM2)

52.8 ± 5.6 nM

5

4. Structure determination. Data processing was carried out with the HKL2000 program suite (8). The structure of DPMI-γ-25-109MDM2 was solved by molecular replacement using Phaser from the CCP4 suite (9) and a search model based on the previously determined structure of 25-

109MDM2 in complex with PMI (3EQS) (3). The electron density of two DPMI molecules present in one asymmetric unit was well defined, allowing full length DPMI to be modeled into the map. The model was further refined with the program Refmac (10), and rebuilt using the program COOT (11). Figure S5. The 2Fo-Fc electron density map of MDM2-bound DPMI-γ, contoured at the 1.1 σ level and displayed on the molecular surface of MDM2.

6

Figure S6. Stereo view of superimposed MDM2-DPMI-γ complexes present in the asymmetric unit. DPMI-γ molecules are shown in ball-and-stick representation, whereas Cα- traces of MDM2 are shown as ribbons. The asymmetric unit of crystal contained two structurally independent MDM2-DPMI-γ complexes related by a twofold axis. Two complexes are essentially identical, with an RMSD of 0.2 Å for all Cα atoms. Figure S7. Putative dimeric assembly of two MDM2-DPMI-γ complexes present in the asymmetric unit. (A) Stereo view of an overall architecture of the putative dimer. MDM2 is shown in pink and gray, whereas DPMI-γ in green and yellow. Helices are represented by cylinders, and residues of the dimer interface are shown as ball-sticks. (B) Close-up view of the putative dimer interface, where only residues involved in dimer formation are shown as ball-sticks. Hydrogen bonds are represented by dots. The putative dimer interface of symmetry related copies involves C-terminal α’ helices of MDM2 and the C-terminal DL10-DR12 stretch of DPMI-γ. Structural analysis by PISA (Protein Interfaces, Surfaces and Assemblies) interactive tool (http://www.ebi.ac.uk/msd-srv/prot_int/pistart.html) suggests that MDM2-DPMI-γ may form a dimer with an average surface area of 2050 Å2 per complex buried. It should be emphasized, however, that no experimental evidence exits for dimerization of the MDM2-DPMI-γ complex in solution. Thus, the dimeric assembly of MDM2-DPMI-γ seen in the crystal structure is likely an artifact resulting from crystal packing.

7

Figure S8. Buried surface area and gained solvation energy, calculated by PISA, of individual residues in DPMI-γ upon complex formation with MDM2. Gained solvation energy is calculated as differences in total solvation energy between isolated and interfacing structures (http://www.ebi.ac.uk/msd-srv/prot_int/pistart.html).

8

5. DAla-scanning mutational analysis. Figure S9. SPR measurements of the binding affinity of DAla-substituted DPMI-γ analogs for 25-

109MDM2. Each curve is the mean of three independent measurements, and the Kd values ± SD are given in the inset. 6. Proteolytic stability. Figure S10. Proteolytic resistance of DPMI-γ. DPMI-γ and its L-enantiomer of identical sequence were incubated at 100 µM each in RPMI 1640 with 25 µg/ml cathepsin G – an intracellular protease with dual specificities for both basic and bulky hydrophobic residues. RP-HPLC was used to monitor and quantify time-dependent peptide hydrolysis. DPMI-γ was completely resistant to cathepsin G at room temperature over a period of 24 hr, whereas the L-enantiomer was quantitatively digested by the enzyme within 8 h. When the experiment was conducted at 37 °C under otherwise identical conditions, the half-life of the L-peptide was less than 10 min. By contrast, no detectable degradation of DPMI-γ was observed for days. These results, while fully expected, demonstrate the superiority of D-peptides over L-peptides with respect to proteolytic stability in vivo.

Kd

D-PMI-MDM2

DPMI 52.8 ± 5.6 nM

W2A 508 ± 19 nM

W3A 819 ± 33 nM

W2A/W3A 467 ± 23 µM

P4A 4.2 ± 0.2 µM

F7A 28.8 ± 1.3 µM

L11A 3.3 ± 0.1 µM

9

7. Cytotoxicity assay. The human colon cancer cell lines HCT116 p53+/+ and HCT116 p53-/- were generously provided by Prof Vogelstein of Johns Hopkins University, and maintained in McCoy’s 5A medium (Invitrogen) supplemented with 10% heat-inactivated FCS and 1% penicillin-streptomycin. Cytotoxic effects of DPMI-γ, DPMI-γ-DR9, DPMI-γ-DR9 negative control, and nutlin-3 on HCT116 cells were evaluated by the standard MTS cell viability assay. Briefly, cells were plated in 96-well plates at a density of 3000 cells/well (100 µL), and, after 24 h, treated with nutlin-3 and various DPMI-γ peptides at different concentrations. Cell viability was measured daily for a period of five days using the CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay Kit (Promega) as per the manufacturer’s protocol. Figure S11. Dose- and time-dependent cytotoxic activity of nutlin-3 (top panel) and DPMI-γ-DR9 (bottom panel) against HCT116 p53+/+ (left column) and HCT116 p53-/- (right column) cells, as determined by the standard MTS cell viability assay. Each curve is the average of two separate experiments.

Nutlin-3

HCT116 p53+/+Nutlin-3

HCT116 p53-/-

DPMI-DR9

HCT116 p53-/-

DPMI-DR9

HCT116 p53+/+

10

Figure S12. Dose- and time-dependent cytotoxic activity of DPMI-γ (top panel) and DPMI-γ-DR9 negative control (bottom panel) against HCT116 p53+/+ (left column) and HCT116 p53-/- (right column) cells, as determined by the standard MTS cell viability assay. Each curve is the average of two separate experiments. For a negative control, the four hydrophobic residues critical for DPMI-γ binding to MDM2 (DTrp2/DTrp3/DPhe7/DLeu11) were all reverted to DAla. The negative control only caused a less than 25% decrease in cell viability at 100 µM, suggesting that the DArg peptide itself was largely non-cytotoxic. 8. Flow cytometric analysis. Necrosis/apoptosis was evaluated by flow cytometric analysis using the PE Annexin V Apoptosis Detection Kit (BD Pharmingen). Briefly, cells were treated with DPMI-DR9 (0, 2.5, 5.0, 10, 20 µM) for 3 or 24 hours, harvested, washed twice with cold PBS, and, then, re-suspended in 1X binding buffer at a concentration of 1 x 106 cells/ml. 100 µl of the solution (1 x 105 cells) was transferred to a 5 ml culture tube, followed by addition of 5 µl of PE Annexin V and 5 µl of 7-AAD. After gentle vortexing and a 15-min incubation in the dark at room temperature, 400 µl of 1X binding buffer was added to the tube, and the cells were analyzed by FACS.

DPMI

HCT116 p53+/+

DPMI

HCT116 p53-/-

DPMI-DR9 neg ctrl

HCT116 p53+/+

DPMI-DR9 neg ctrl

HCT116 p53-/-

11

Figure S13. Effects of DPMI-γ-DR9 on HCT116 cells as determined by flow cytometric analysis. Viable cells are PE Annexin V and 7-AAD negative; cells in early apoptosis are PE Annexin V positive and 7-AAD negative; and cells that are in late apoptosis or already dead are both PE Annexin V and 7-AAD positive. Lack of significantly populated cells in early apoptosis suggests a primarily necrotic cell death mechanism. Analysis was performed 3 or 24 hours after HCT116 cells were treated with DPMI-γ-DR9 varying two-fold from 20 to 2.5 µM. As shown in, at both time points, 50% of the cells died in the presence of 5-10 µM of DPMI-γ-DR9, where only a small fraction of cells appeared in early apoptosis (PE Annexin V positive, 7-AAD negative).

73.5%48.7%22.4%10.2%6.6%

82.0%70.9%29.7%11.0%4.6%

82.8%71.7%36.4%8.1%5.2%

72.6%58.7%24.3%6.7%7.1%

HC

T116 p53+/+

, 24 h

rsH

CT

11

6 p53+/+

, 3

hrs

HC

T1

16

p53-/- , 3

hrs

HC

T1

16

p53-/- , 2

4 h

rs

DPMI-DR9, 2.5 µM DPMI-DR9, 5.0 µM DPMI-DR9, 10 µM DPMI-DR9, 20 µMUntreated

100 101 102 103 104 101 102 103 104 101 102 103 104 101 102 103 104101 102 103 104100

101

102

103

104

101

102

103

104

101

102

103

104

101

102

103

104

PE Annexin V

7-AAD

12

9. Liposome Preparation Materials. Hydrogenated soybean phosphatidylcholine and phosphatidylethanolamine distearoyl methoxypolyethylene glycol 2000 conjugate (mPEG2000-DSPE) were purchased from Lipoid GmbH (Ludwigshafen, Germany) and Sigma (St. Louis, MO, USA) respectively. Cholesterol was purchased from Shanghai Chemical Reagent Company (Shanghai, China) and maleimide-derivatized PEG-DSPE (Mal-PEG3400-DSPE) from Laysan Bio, Inc. (AL, USA). All Boc-amino acids and Fmoc-amino acids were purchased from Peptides International and Bachem. All other reagents and chemicals were of analytical grade or better and were used without further purification. Peptide synthesis. Chemical synthesis of DPMIα (sequence: TNWYANLEKLLR) and its L-enantiomer was carried out using standard Boc-solid phase peptide synthesis methods. The preparation of cyclic pentapeptide c(RGDDYK) was carried out as previously described (12). Briefly, the linear peptide H-Asp(OtBu)-DTyr(OtBu)-Lys(Boc)-Arg(Pbf)-Gly-OH, obtained via Fmoc-solid phase peptide synthesis, was cyclized by PyBOP and deprotected by trifluoroacetic acid. All crude peptides were purified by preparative RP-HPLC to homogeneity, and their molecular masses were ascertained by ESI-MS. Synthesis of cyclic-RGD-PEG3400-DSPE. Cyclic-RGD-PEG3400-DSPE was synthesized by coupling thioacetylated c(RGDDYK) with MAL-PEG3400-DSPE. Thiolation of c(RGDDYK) was achieved by using the N-Succinimudyl-S-acetylthiopropionate (SATP) reagent (Pierce, USA) per the manufacturer’s protocol with minor modifications. In brief, 1.0 ml of c(RGDDYK) at 15 mg/ml in 0.1M PBS buffer, pH 7.2, was mixed with 12 mg SATP dissolved in 20 μl DMF. After a one-hour incubation at room temperature, the modified peptide was purified by preparative HPLC, lyophilized and deacetylated in 2 ml PBS buffer with 200 μl deacetylation solution. The resultant sulfhydryl-modified peptide was purified and lyophilized. For the preparation of c(RGDDYK)-PEG3400-DSPE, 10 mg MAL-PEG3400-DSPE was dissolved in 1 ml DMF and mixed with 2 mg thioacetyl c(RGDDYK) in 3 ml PBS solution at pH 7.5. The mixture was sonicated to remove bubbles produced, and incubated for 1 h at room temperature. Un-reacted thiopropionic c(RGDDYK) was removed by ultrafiltration (MWCO 3500) against distilled water as monitored by RP-HPLC. The conjugate was characterized and verified by 1H-NMR spectroscopy (Figure S14). Preparation of liposomes. Peptide-loaded liposomes were prepared using the conventional reverse phase evaporation techniques as reported previously with minor modifications (13). HSPC, cholesterol, mPEG2000-DSPE and c(RGDDYK)-PEG3400-DSPE were mixed in chloroform at a molar ratio of 55:45:2:1, yielding a 2 ml organic phase containing 40 mg of liposomal membrane materials. DPMIα (6 mg) was dissolved in 300 µl saline and added to the organic solution, followed by sonication to make a steady emulsion. The organic solvent in the thick emulsion was removed by a rotary evaporator, to which 3.7 ml saline was added for hydration at 37 °C for 30 min. The suspension was repeatedly extruded through polycarbonate membranes with 200, 100 and 80 nm pore sizes successively, using a mini-extruder (Avanti Polar Lipid, AL). For in vitro and in vivo bioactivity assays, peptide-loaded liposomes were purified on a Sephadex CL-4B column equilibrated with saline buffer. The concentration of encapsulated peptide was determined by RP-HPLC after extraction using acidified isopropanol (14). The

13

purified liposomes can be further concentrated through ultrafiltration (MWCO 10,000 Millipore, USA) to obtain higher concentrations of encapsulated peptide as required. The c(RGDDYK)-liposomal doxorubicin, as the positive control for in vivo assays, was prepared by the active-loading ammonium sulfate method (15). Peptide encapsulation efficiency. To determine the encapsulation efficiency, the liposomes without chromatographical purification were directly centrifuged at 50,000 g for 30 min at 4 °C. The peptide concentration in the supernatant was determined by RP-HPLC, using a calibration curve (R2>0.998) generated under the same conditions with the peptide of known concentrations. The encapsulation efficiency was calculated as ratio of free peptide in the supernatant to the total amount of peptide. The mean particle diameter was 90 nm for the RGD-liposome-DPMIα (polydispersity, 0.17), and the encapsulation efficiency was 32.5 ± 1.9%.

Figure S14. NMR spectra of MAL-PEG3400-DSPE and c(RGDDYK)-PEG3400-DSPE at 400 MHz. The disappearance of MAL at 6.7 ppm suggests that c(RGDDYK)-PEG3400-DSPE contains no unreacted MAL-PEG3400-DSPE .

14

10. Comparison between U87 and U251 cells.

Figure S15. Human glioma cell line U251 is insensitive to the treatment of RGD-liposome-DPMIα as determined by the MTT cell viability assay. The data are averages of three independent experiments. 11. In vivo near-infrared fluorescence imaging of U87 intracranial xenografts in nude mice. In situ tumor-bearing mice, 14 days after inoculation, were injected with 200 μl of DiR encapsulated cyclic-RGD liposome via tail vein (DiR = 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide). Images were collected 2 h after injection using an in-vivo image system (Multispectral, Kodak, USA) equipped with filter sets (excitation/emission, 730/790 nm) (16).

liver kidney spleen

heart lung brain

glioblastoma

liver kidney spleen

heart lung brain

glioblastoma

15

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crystal structures. Nature 355(6359):472-475. 2. Schnolzer M, Alewood P, Jones A, Alewood D, & Kent SB (1992) In situ neutralization

in Boc-chemistry solid phase peptide synthesis. Rapid, high yield assembly of difficult sequences. Int J Pept Protein Res 40(3-4):180-193.

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8. Otwinowski Z, Minor W, & Carter J, C.W. eds (1997) (Academic Press), pp 307-326. 9. Storoni LC, McCoy AJ, & Read RJ (2004) Likelihood-enhanced fast rotation functions.

Acta Crystallogr D Biol Crystallogr 60(Pt 3):432-438. 10. Murshudov GN, Vagin AA, & Dodson EJ (1997) Refinement of macromolecular

structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 53(Pt 3):240-255.

11. Emsley P & Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60(Pt 12 Pt 1):2126-2132.

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13. F.C. Szoka, D. Papahadjopoulos (1978). Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc Natl Acad Sci USA 75:4194-4198.

14. Q. Ye, J. Asherman, M. Stevenson, E. Brownson, N.V. Katre (2000). DepoFoam technology: a vehicle for controlled delivery of protein and peptide drugs. J Control Release 64:155-166.

15. Hong Pan, Limei Han, Wei Chen, Ming Yao, Weiyue Lu (2008). Targeting to tumor necrotic regions with biotinylated antibody and streptavidin modified liposomes. J Control Release 125(3):228-235.

16. Q. Meng, M. Yu, B. Gu, J. Li, Y. Liu, C. Zhan, C. Xie, J. Zhou, W. Lu (2010). Myristic acid-conjugated polyethylenimine for brain-targeting delivery: in vivo and ex vivo imaging evaluation. J Drug Target (in press)