protein surface recognition and proteomimetics: mimics of protein surface structure and function

Protein surface recognition and proteomimetics: mimics ofprotein surface structure and functionSteven Fletcher and Andrew D Hamilton

Due to their key roles in a number of biological processes,

protein–protein interactions are attractive and important

targets, typically involving areas greater than 6 nm2. The

disruption of such interactions remains a challenging feat but,

in recent years, there has been considerable progress in the

design of proteomimetics: molecules that mimic the structure

and function of extended regions of protein surfaces. In

particular, porphyrins, calixarenes, a-helical mimetics and

small molecules have successfully modulated significant

protein–protein interactions, including those involved in cancer

and HIV.

Addresses

Department of Chemistry, Yale University, CT 06520-8107, USA

Corresponding author: Hamilton, Andrew D ([email protected])

Current Opinion in Chemical Biology 2005, 9:632–638

This review comes from a themed issue on

Model systems

Edited by Paolo Scrimin and Lars Baltzer

Available online 18th October 2005

1367-5931/$ – see front matter

# 2005 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.cbpa.2005.10.006

IntroductionProtein–protein interactions play key roles in several bio-

logical processes, such as cell proliferation, growth and

differentiation, and these interactions are therefore attrac-

tive targets for the chemical biologist [1]. However, the

disruption of protein–protein interactions remains a diffi-

cult challenge, primarily because of the large interfacial

area required for specific recognition (typically > 6 nm2 is

buried during a protein–protein interaction), as well as the

unique topological distribution of charged, polar and

hydrophobic residues on the protein surface. Nonetheless,

there have been many studies reporting some success in

this field [2–5]. In this review, we focus on recent advances

of protein recognition by compounds that mimic protein

surface structure and function: proteomimetics.

Porphyrins, peptidocalixarenes andmetal-based systemsObserving that cytochrome c (cyt c) interacts with its

redox partners (e.g. cytochrome c oxidase) predominantly

through a hydrophobic patch that is surrounded by invar-

iant Arg and Lys residues, Hamilton et al. designed


tetracarboxyphenylporphyrin derivatives bearing anionic

side chains to complement the distribution of function-

ality on the protein surface. The authors have successfully

prepared low nanomolar binders of cyt c (Ki = 20 nM) [6],

which can be improved to subnanomolar binders by

extending the hydrophobic core scaffold of tetraphenyl-

porphyin (diameter = 15.5 A) to the wider 24.0 A tetra-

biphenylporphyrin scaffold and by increasing the number

of peripheral anionic groups from 8 to 16 (Ki = 0.67 nM,

Figure 1a) [7]. Furthermore, some of these anionic por-

phyrins have been shown to denature cyt c through

binding-induced disruption of tertiary and secondary

structure [8,9], thereby leading to accelerated proteolytic

degradation [10�].

Trauner and co-workers have similarly described the use

of porphyrins to match the symmetry of the homotetra-

meric human Kv1.3 potassium channel [11]. A large

variety of potassium channel inhibitors have been iden-

tified, although all bind the pore region of the protein and

do not take advantage of its inherent fourfold symmetry.

Trauner et al. proposed that the molecular architecture

provided by tetracarboxyphenylporphyrin derivatives

could also allow for pore binding by the central porphyrin

scaffold. Moreover, its four peripheral acids could be

derivatized with cationic groups simultaneously project-

ing towards highly conserved Asp or Glu ‘hot spot’

residues in each of the channel subunits, leading to a

strong polyvalency effect. Indeed, the authors demon-

strated, by competitive binding studies, that their cationic

porphyrins strongly interact, in the nanomolar range, with

the potassium channel, and, as determined by electro-

physiological measurements, significantly reduce the cur-

rent through the channel (Figure 1b). Further work in this

area may lead to novel therapeutic agents against diseases

such as diabetes and epilepsy.

In a popular area of research [12,13] there have been

recent reports on protein surface recognition by peptido-

calixarenes. Cunsolo et al. have designed basic amino acid

calix[8]arene receptors that behave as competitive inhi-

bitors of recombinant human tryptase, probably binding

the intended region of Asp residues near the active sites

of the tetrameric protein [14]. Neri et al. recently demon-

strated the surface recognition of transglutaminase by

their peptidocalix[4]arene diversomers (isomers compris-

ing the same components that are arranged in different

orders) [15]. Again, competition assays suggest their inhi-

bitors bind to a surface area of the protein (‘hot spot’)

other than the enzyme active site, exerting their inhibi-

tory effects either by causing a conformational change in

www.sciencedirect.com

Protein surface recognition and proteomimetics Fletcher and Hamilton 633

Figure 1

Tetracarboxyphenylporphyrin derivatives that recognize the surfaces of (a) cytochrome c (Kd = 0.67 nM) [7] (cationic residues are shown as black

spheres), and (b) the human Kv1.3 potassium channel (Ki = 20 nM) [11]. Overlays of the likely interactions of the porphyrin scaffolds with the

two proteins are shown. Structures reproduced with permission. Part (a), Copyright 2003, Elsevier. Part (b), Copyright 2003, The American

Chemical Society.

the active protein or perhaps by acting as steric blocks,

hindering the approach of the substrate. In 2003, Wimmer

and co-workers showed by NMR spectroscopy that b-

cyclodextrin recognizes insulin by admitting a solvent-

exposed aromatic side chain into its cavity [16].

Recently, Hamachi et al. designed molecules incorporat-

ing palladium or zinc that, in a sequence-selective fash-

ion, recognize histidine and phosphorylated amino acid

residues on peptide surfaces [17�,18]. In both cases, the

synthetic molecules modified the a-helicities of various

17-mer peptides, as monitored by CD spectroscopy, by

crosslinking two identical side-chains via cooperative

metal–ligand interactions. For histidine recognition, a

Pd(II)–ethylenediamine dinitrate complex stabilized

the a-helical conformation when the His residues of

the peptide were at a distance of i and i + (3 or 4), whereas

their dipicolylamine Zn(II) complex recognized His resi-

dues that were further apart. Although referring only to

short peptide chains, these results clearly illustrate that

metal–ligand interactions are capable of selectively recog-

nizing (and sensing) [18] protein surfaces, as had been

shown previously by Mallik [19].

Rotello et al. have described a novel approach to surface

binding and the reversible inhibition of a-chymotrypsin

(ChT) by using mercaptoundecanoate-functionalised

gold nanoparticles [20]. These anionic mixed-monolayer

protected clusters (MMPCs) bind to the cationic residues

that encircle the active site of the enzyme, sterically

blocking the entrance of a substrate and causing dena-


turation of ChT, presumably due to prolonged exposure

to the hydrophobic monolayer of fatty acids. Modification

of the protein conformation may be undesirable, so, in

further work [21��], the authors tailored the mercaptoun-

decanoic acid ligands to include a tetraethylene glycol

spacer in the hope that their nanoparticles would exhibit

increased hydrophilicity and prevent ChT denaturation.

Indeed, the resulting ligands were capable of binding

ChT, with no disruption of protein conformation. See also

the review by You, De and Rotello, in this issue.

a-Helical mimeticsHamilton et al. have introduced 3,20,20-functionalised

terphenyl derivatives as structural and functional

mimetics of a-helices with the preparation of two potent

antagonists of calmodulin (IC50 values of 9 nM and

20 nM) [22], and inhibitors of the assembly of the hex-

americ HIV fusion protein gp41 [23]. More recently, they

have designed an a-helix mimetic scaffold based on an

oligoamide-foldamer strategy to target the interaction of

the pro-apoptotic protein Bak with the anti-apoptotic

protein Bcl-xL [24�]. Their trispyridylamide scaffold

(Figure 2a) exhibits a preferred conformation with all

O-substituents (here, iso-propoxy groups) projected on

the same side of the molecule — analogous to the i, (i + 4)

and (i + 7) residues in the a-helix — in this case due to the

preorganizing bifurcated hydrogen-bonding network,

thereby mimicking the a-helical BH3 domain of Bak.

The authors reported several inhibitors of the Bak BH3–

Bcl-xL interaction in the low micromolar range. Further

work with their terphenyl scaffold led to the development


634 Model systems

Figure 2

Alternative (a) trispyridylamide (Ki = 2.30 mM) [24�] and (b) terephthalamide (Ki = 1.85 mM) [27��] a-helical mimetics of the Bak BH3 peptide

that target Bcl-xL, and (c) superimposition of the generic terephthalamide scaffold on the i, (i + 4) and (i + 7) residues of an a-helix.

of low micromolar inhibitors of the p53–HDM2 (human

double minute 2) interaction, an attractive strategy for the

development of anti-cancer drugs [25�]. By conducting15N HSQC experiments, the authors concluded that their

mimetics of the a-helical region of p53 project their side

chains into the F19, W23 and L26 binding pockets of

HDM2. Moreover, one of their inhibitors exhibits a 14-

fold and an 82-fold selectivity over the Bak-Bcl-xL and

Bak-Bcl-2 interactions, respectively. With an alternative,

less synthetically-challenging terephthalamide scaffold,

Hamilton and Yin have developed simpler and more

water soluble submicromolar inhibitors (Ki = 0.78 mM

and 1.85 mM (Figure 2b)) of the Bak–Bcl-xL interaction

[26,27��]. In addition, treatment of HEK293 cells with the

compound shown in Figure 2b led to disruption of the

Bax (a Bak-analogue)–Bcl-xL interaction with an IC50 of

35 mM [27��]. An energy-minimized alignment of the

alkyl groups of the terephthalamide scaffold with the

side chains of the i, (i + 4) and (i + 7) residues of an a-

helix is depicted in Figure 2c.

Schepartz et al. have also targeted the p53–HDM2 inter-

action with b3-peptides, which have one more carbon

atom than their a-peptide counterparts and a concomitant

resistance to metabolism and proteolysis. Their set of b3-

peptides exhibits significant helix-14 structure in water,

and one oligomer binds HDM2 selectively and with

nanomolar affinity [28]. In addition, Robinson et al. have

designed cyclic b-hairpin molecules that mimic the p53

helix, and have reported submicromolar IC50 values for

the disruption of the p53–HDM2 interaction [29�].

A recent study by Verdine and co-workers describes very

successful efforts towards targeting the interaction


between BID and Bcl-xL by generating ‘hydrocarbon-

stapled’ helices, based on the amphipathic a-helical BH3

domain of BID [30��]. By incorporating a,a-disubsti-

tuted, non-natural amino acids with terminal olefinic side

chains at positions i and (i + 4) or i and (i + 7) of the BH3

peptide, two reactive olefins were positioned on the same

face of the a-helix. Ruthenium-catalyzed ring-closing

metathesis generated macrocyclic derivatives with sub-

stantially increased a-helical content from 16% in the

unmodified BH3 peptide to as much as 87% in one

modified peptide. Furthermore, this introduction of a

hydrophobic constraint led to a sixfold increase in binding

affinity (Kd = 38.8 nM compared with 269 nM) and

afforded protease resistance and cell permeability. Upon

administration to Jurkat T cell leukemia cells, the con-

strained helix induced apoptosis, and in vivo the growth of

human leukemia xenografts was inhibited.

An elegant means of disrupting protein–protein interac-

tions by implementing a protein grafting strategy has

been reported by Schepartz et al. [31]. The authors

describe the use of the small, yet well-folded, avian

pancreatic polypeptide (aPP) as a scaffold to present

functional epitopes of larger proteins on its a-helix by

substitution of amino acid residues. The resultant min-

iature proteins, which may be generated with or without

directed evolution, have been shown to bind — in the

nanomolar range — a variety of protein targets (as well as

duplex DNA), such as the related anti-apoptotic proteins

Bcl-2 and Bcl-xL [31,32], and the EVH1 domain of the

cytoskeletal protein Mena [33]. In 2005, Schepartz, Wood

and co-workers took their protein grafting technology one

stage further [34�]. The authors grafted the cAMP-depen-

dent protein kinase (PKA) recognition epitope of protein



kinase inhibitor (PKI) onto the a-helix of aPP, leading to

a miniature protein that recognizes PKA with nanomolar

affinity. They then conjugated the C-terminal cysteine

residue of the miniature protein to a high affinity but non-

selective kinase active site inhibitor (K252a). The com-

plementary effects of protein surface recognition and

active site binding led to the identification of a potent

protein–inhibitor conjugate that exhibits increased kinase

specificity, relative to free K252a.

Small molecule inhibitors of protein–proteininteractionsChmielewski and co-workers reported in 2004 that a

focused library approach led to the generation of potent,

small-molecule dimerization inhibitors of HIV-1 protease

(Ki = 71 nM; Figure 3a) [35��]. More importantly, how-

ever, their protein surface inhibitors were equipotent with

wild-type HIV-1 protease and a mutant form of the

enzyme that is drug-resistant to active-site-directed inhi-

bitors, suggesting a promising alternative to active-site-

directed inhibition in anti-HIV therapy. The ZipA–FtsZ

protein–protein interaction, which is a potential target for

antibacterial therapy, has been investigated recently by

Jennings et al. at Wyeth Research. Through HSQC NMR

experiments, the authors have confirmed that their sub-

stituted 3-(2-indolyl)piperidines and 2-phenylindoles

bind to the FtsZ binding domain of ZipA, thereby block-

ing the interaction with FtsZ and leading to inhibition of

cell division, as determined by a cell elongation assay [36].

In 2003, Guy et al. reported the first specifically targeted

irreversible inhibitor of a protein–protein interaction [37�].The authors prepared a 3-hydroxymethylindole derivative

(Figure 3b), designed to bind to the second PDZ domain

Figure 3

Small molecule inhibitors of (a) the dimerization of HIV-1 protease (Ki = 71 n


of MAGI3, a protein that binds to the tumor suppressor

protein PTEN. Furthermore, DOCKing experiments sug-

gested that the weakly ionizable hydroxyl group of the

inhibitor may alkylate the nearby His372. Indeed, their

results are consistent with irreversible inhibition, which

is almost certainly due to functionalization of His372.

To disrupt the interaction of the third PDZ domain of

PSD-95 with the NMDA receptor, Spaller et al. have

synthesized a series of lactam-constrained peptides

through bridging side chains, such as Lys and Glu. The

lactam ring sizes may be readily expanded or contracted

through variation of the bridging component, thereby

enabling some conformational variety [38]. Isothermal

calorimetry (ITC) was used to determine the thermody-

namic parameters of the inhibitor–PDZ interactions; many

Kd values were in the low micromolar range (<50 mM).

Todd et al. have successfully created non-peptidic small

molecules (for an example, see Figure 3c) with a novel

bis-imidazole scaffold that are capable of reversibly dis-

rupting the binding of the hepatitis C virus (HCV)

envelope glycoprotein E2 to its receptor partner CD81,

by mimicking the spatial and hydrophobic features of

helix D of CD81 [39]. By analysis of the Connolly surface

of the insulin–insulin-receptor complex, Kotra and Batey

et al. have synthesized small molecules that mimic the

interaction of insulin with its receptor [40]. Their lead

compound contains a hydantoin core with three side

chains: a phenyl group, a carboxylic acid, and an amine,

intended to mimic the ‘key’ interaction residues of insu-

lin (TyrB16, GluB21 and Arg22, respectively).

Based on the 21-mer IB peptide of ICAM-1, Siahann et al.have prepared cyclic peptides that inhibit the ICAM-1/

M) [35��], (b) MAGI3–PTEN [37�] and (c) HCV-E2–CD81 [39].


636 Model systems

LFA-1-mediated T-cell adhesion to epithelial cells [41].

Their results suggest that the Pro-Arg-Gly sequence may

be important for binding to LFA-1. In addition, Burris and

Wittliff et al. have demonstrated selective inhibition of

the estrogen receptor–protein coactivator interaction with

constrained, cyclic peptides that were designed to exhibit

a-helicity [42�]. A lactam, bridged through Glu and Lys

side chains, binds estrogen receptor with a Ki of 220 nM,

and a disulfide-linked peptide binds even more potently

(Ki = 25 nM).

Genetic screening systems for smallmolecule inhibitorsShen et al. have demonstrated that a mammalian two-

hybrid genetic system is capable of screening for small

molecules that are able to disrupt protein–protein inter-

actions [43��]. The two interacting proteins are fused

either to a DNA-binding domain or a transcriptional acti-

vator. When the two proteins interact, reporter genes such

as green fluorescent protein (GFP) are expressed; in the

presence of a small molecule drug that interferes with the

protein–protein interactions, the reporter genes are

silenced. Using this system, Shen and co-workers have

identified a molecule that can directly block the R1–FKBP

interaction and a molecule that can indirectly disrupt the

EGFR–p85 interaction by acting as a kinase inhibitor.

Protein fingerprintingUsing an array of fluorescent protein surface receptors,

Hamilton et al. have described a simple ‘naked eye’

detection approach to the recognition of different pro-

teins [44�]. In a ‘one-pot’ synthesis, meso-tetracarboxy-

phenylporphyrin was derivatized with two different

amino acids or amino acid derivatives, giving a mixture

of six unique products. Iteration of this procedure with

further amino acids and/or derivatives led to a library of 35

unique fluorophores, exhibiting peripheral charges from –

8 to +8, and with four to eight hydrophobic groups. When

incubated with different proteins, an array of eight of the

porphyrins interacted differently with the various pro-

teins, thereby generating a characteristic fingerprint for

each protein. Such protein-detecting arrays may prove

important in biomedical applications.

An alternative protein fingerprinting system was

described recently by Schrader and Zadmard, who have

developed a nanomolar protein sensing system using

charged calix[4]arene derivatives embedded in a stearic

acid monolayer [45�]. The authors prepared tetrapho-

sphonate-, benzylammonium- and anilinium-derivatised

calixarenes through simple synthetic procedures, thereby

creating acidic, basic and partially basic NH2/NH3+ ‘cha-

meleon’ receptors, respectively. Due to non-saturation of

the monolayers, the authors argue that upon subinjection

of a complementarily charged protein, receptor molecules

in solution are captured and charge-neutralized. This

renders the receptor more lipophilic such that the whole


complex becomes reincorporated into the monolayer,

thereby accounting for the observed increases in the

surface area of the monolayer. Since different proteins

show distinct interactions with the different monolayers

— an event which is largely governed by protein sizes and

pI values — the size increase (or decrease) of the mono-

layers serves as a pattern recognition for the proteins.

ConclusionsAlthough the development of protein–protein interaction

inhibitors is still in its infancy, there has been recent

notable progress, heralding a novel and alternative

approach to traditional medicinal chemistry. In particular,

preliminary studies suggest that the resistance to active

site-directed drugs may be overcome with surface recog-

nition (and inhibition of dimerization) of HIV-1 protease,

and that anionic porphyrins can denature cyt c, paving the

way for the development of ‘conformational drugs’ that

could regulate protein function by altering protein struc-

ture. In addition, peptidic and non-peptidic synthetic

molecules, as well as modified miniature proteins, are

proving to be potent a-helical mimetics, restricting HIV-1

cell entry and disrupting such interactions as Bak–Bcl-xL

and p53–HDM2. Taken together, these results hold good

promise for the development of novel therapeutics that

can exploit the large, varied and highly functionalized

surfaces involved in protein–protein interactions.

UpdateGellman et al. have prepared tight binding ligands

(Ki = 0.7 nM) to disrupt the Bak–Bcl-xL interaction

[46�]. By creating chimeric (a/b + a)-peptides with dis-

crete folding propensities, the authors have mimicked the

a-helical display of Bak side chains. Moreover, these

foldamers are probably proteolytically stable, conferring

an advantage over a-peptide inhibitors.

AcknowledgementsThe authors wish to thank the National Institutes of Health for supportof their work in this area, and Debarati Mazumder and ChristopherCummings for critical reading of this manuscript.

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest�� of outstanding interest

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10.�

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Design of anionic metalloporphyrins to complement the principal inter-action surface of cyt c led to the development of synthetic denaturants.

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14. Mecca T, Consoli GM, Geraci C, Cunsolo F: Designedcalix[8]arene-based ligands for selective tryptase surfacerecognition. Bioorg Med Chem 2004, 12:5057-5062.

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17.�

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21.��

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CdSe nanoparticle scaffolds presenting thioalkyl and thioalkylated oli-go(ethylene glycol) ligands afforded three different chymotrypsin recog-nition systems: no interaction, inhibition with denaturation and inhibitionwith retention of conformation.

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of extended regions of an a-helix. J Am Chem Soc 2001,123:5382-5383.

23. Ernst JT, Kutzki O, Debnath AK, Jiang S, Lu H, Hamilton AD:Design of a protein surface antagonist based on a-helixmimicry: inhibition of gp41 assembly and viral fusion.Angew Chem Int Ed Engl 2002, 41:278-281.

24.�

Ernst JT, Becerril J, Park HS, Yin H, Hamilton AD: Design andapplication of an a-helix-mimetic scaffold based on anoligoamide-foldamer strategy: antagonism of the Bak BH3/Bcl-xL complex. Angew Chem Int Ed Engl 2003, 42:535-539.

Low micromolar trispyridylamide a-helix mimetics disrupt the Bak–Bcl-xL

interaction.

25.�

Yin H, Lee GI, Park HS, Payne GA, Rodriguez JM, Sebti SM,Hamilton AD: Terphenyl-based helical mimetics that disruptthe p53/HDM2 interaction. Angew Chem Int Ed Engl 2005,44:2704-2707.

The synthesis and inhibition potencies of the p53–HDM2 interaction by aseries of terphenyl-based helical mimetics are described. One terphenylderivative binds HDM2 with submicromolar affinity and exhibits an 82-fold selectivity over Bcl-2.

26. Yin H, Hamilton AD: Terephthalamide derivatives as mimeticsof the helical region of Bak peptide target Bcl-xL protein.Bioorg Med Chem Lett 2004, 14:1375-1379.

27.��

Yin H, Lee GI, Sedey KA, Rodriguez JM, Wang HG, Sebti SM,Hamilton AD: Terephthalamide derivatives as mimetics ofhelical peptides: disruption of the Bcl-x(L)/Bak interaction.J Am Chem Soc 2005, 127:5463-5468.

A series of terephthalamide derivatives as helical mimetics was prepared.Many derivatives exhibit low micromolar activity in disrupting the Bak–Bcl-xL interaction, and one derivative disrupts the interaction in wholecells with an IC50 of 35 mM.

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29.�

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Submicromolar IC50 values are reported for a series of b-hairpin mole-cules that mimic the a-helical region of p53, disrupting the p53–HDM2interaction.

30.��

Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD,Wagner G, Verdine GL, Korsmeyer SJ: Activation of apoptosis invivo by a hydrocarbon-stapled BH3 helix. Science 2004,305:1466-1470.

BH3 peptides with improved pharmacological properties were synthe-sized and shown to be potent disruptors of the Bcl-xL–BID interactions.Moreover, inhibition of the growth of human leukemia xenografts in vivo isreported.

31. Chin JW, Schepartz A: Design and Evolution of a Miniature Bcl-2 Binding Protein. Angew Chem Int Ed Engl 2001, 40:3806-3809.

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33. Golemi-Kotra D, Mahaffy R, Footer MJ, Holtzman JH, Pollard TD,Theriot JA, Schepartz A: High affinity, paralog-specificrecognition of the Mena EVH1 domain by a miniature protein.J Am Chem Soc 2004, 126:4-5.

34.�

Schneider TL, Mathew RS, Rice KP, Tamaki K, Wood JL,Schepartz A: Increasing the kinase specificity of K252a byprotein surface recognition. Org Lett 2005, 7:1695-1698.

The kinase specificity of K252a is increased by conjugation to a miniatureprotein that presents the cAMP-dependent protein kinase recognitionepitope.

35.��

Shultz MD, Ham YW, Lee SG, Davis DA, Brown C, Chmielewski J:Small-molecule dimerization inhibitors of wild-type andmutant HIV protease: a focused library approach. J Am ChemSoc 2004, 126:9886-9887.

A library of compounds that target the HIV-1 protease dimerizationinterface is described. Importantly, their dimerization inhibitors are equi-potent with mutant forms of HIV-1 protease that are impervious to activesite-directed inhibitors.


638 Model systems

36. Jennings LD, Foreman KW, Rush TS III, Tsao DH, Mosyak L,Kincaid SL, Sukhdeo MN, Sutherland AG, Ding W, Kenny CH et al.:Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA-FtsZ interaction. Bioorg Med Chem 2004, 12:5115-5131.

37.�

Fujii N, Haresco JJ, Novak KA, Stokoe D, Kuntz ID, Guy RK:A selective irreversible inhibitor targeting a PDZ proteininteraction domain. J Am Chem Soc 2003, 125:12074-12075.

Using structure-based design, an inhibitor was synthesized that blocksligand binding to the MAGI3 PDZ2 domain irreversibly.

38. Li T, Saro D, Spaller MR: Thermodynamic profiling ofconformationally constrained cyclic ligands for the PDZdomain. Bioorg Med Chem Lett 2004, 14:1385-1388.

39. VanCompernolle SE, Wiznycia AV, Rush JR, Dhanasekaran M,Baures PW, Todd SC: Small molecule inhibition of hepatitis Cvirus E2 binding to CD81. Virology 2003, 314:371-380.

40. Tan C, Wei L, Ottensmeyer FP, Goldfine I, Maddux BA, Yip CC,Batey RA, Kotra LP: Structure-based de novo design of ligandsusing a three-dimensional model of the insulin receptor.Bioorg Med Chem Lett 2004, 14:1407-1410.

41. Anderson ME, Yakovleva T, Hu Y, Siahaan TJ: Inhibition of ICAM-1/LFA-1-mediated heterotypic T-cell adhesion to epithelialcells: design of ICAM-1 cyclic peptides. Bioorg Med Chem Lett2004, 14:1399-1402.

42.�

Leduc AM, Trent JO, Wittliff JL, Bramlett KS, Briggs SL,Chirgadze NY, Wang Y, Burris TP, Spatola AF: Helix-stabilizedcyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. Proc Natl Acad Sci USA 2003,100:11273-11278.


Lactam and disulfide cross-linked cyclic peptides exhibit potent inhibitionof the estrogen–coactivator interaction.

43.��

Zhao HF, Kiyota T, Chowdhury S, Purisima E, Banville D, Konishi Y,Shen SH: A mammalian genetic system to screen for smallmolecules capable of disrupting protein-protein interactions.Anal Chem 2004, 76:2922-2927.

By fusing the two interacting proteins to a DNA binding domain or atranscriptional activator, small-molecule inhibitors of the R1–FKBP andEGFR–p85 interactions led to reporter gene silencing.

44.�

Baldini L, Wilson AJ, Hong J, Hamilton AD: Pattern-baseddetection of different proteins using an array of fluorescentprotein surface receptors. J Am Chem Soc 2004,126:5656-5657.

The synthesis of an array of porphyrins by a simple one-pot procedure isdescribed. Eight members of the porphyrin library are shown to interactdistinctively with a range of proteins thereby generating characteristicprotein fingerprints.

45.�

Zadmard R, Schrader T: Nanomolar protein sensing withembedded receptor molecules. J Am Chem Soc 2005,127:904-915.

An alternative protein fingerprinting system to that described in [44�] usescharged calix[4]arenes embedded in a stearic acid monolayer. Thissystem detects proteins as low as picomolar concentrations.

46.�

Sadowsky JD, Schmitt MA, Lee H-S, Umezawa N, Wang S,Tomita Y, Gellman SH: Chimeric (a/b + a)-peptide ligandsfor the BH3-recognition cleft of Bcl-xL: critical role of themolecular scaffold in protein surface recognition. J Am ChemSoc 2005, 127:11966-11968.

Chimeric (a/b + a)-peptides are described that disrupt the Bak–Bcl-xL

interaction with subnanomolar affinity.


protein surface recognition and proteomimetics: mimics of protein surface structure and function

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