C O M M U N I C A T I O N S
Since essentially the same instrument used here has been employed
to synthesize high-density arrays of DNA oligonucleotides,26 we
anticipate that spatially defined arrays of up to 100 000 peptoids
can be constructed using the technology described here. The
photolithographic synthesis of these large libraries of peptoids
constructed from a variety of amines is underway and will be
reported in due course. We anticipate that these small-molecule
arrays will be of considerable utility in the isolation of protein-
binding agents.
Acknowledgment. We thank Jennifer M. Vrtis for proofreading
and comments on the manuscript. Funds for the construction of
the digital optical chemistry instrument used in these experiments
were provided by a contract from the National Heart Lung and
Blood Institute (NO1-HV-28185).
Supporting Information Available: Synthesis of compounds and
detailed experimental protocol. This material is available free of charge
Figure 2. Time-dependent deprotection of MeNPOC groups on a glass
slide. The upper image shows the fluorescent intensities of different areas
on the slide where MeNPOC-groups were photodeprotected for different
times and then labeled with Cy3-phosphoramidite. The bottom is the
correlation between the fluorescent intensities of these areas and the time
of UV irradiation. This curve indicates that maximum removal of the
MeNPOC group is achieved after 10 min of exposure to 365 nm UV light
at 2 mW/cm2.
References
(1) Schreiber, S. L. Chem. Eng. News 2003, 81, 51-61.
(2) Schreiber, S. L. Biorg. Med. Chem. 1998, 6, 1127-1152.
(3) Kodadek, T. Chem. Biol. 2001, 8, 105-115.
(4) Kodadek, T. Trends Biochem. Sci. 2002, 27, 295-300.
(5) Kuruvilla, F. G.; Shamji, A. F.; Sternson, S. M.; Hergenrother, P. J.;
Schreiber, S. L. Nature 2002, 416, 653-657.
(6) Lam, K. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmierski, W.
M.; Knapp, R. J. Nature 1991, 354, 82-84.
(7) MacBeath, G.; Koehler, A. N.; Schreiber, S. L. J. Am. Chem. Soc. 1999,
121, 7967-7968.
(8) Olivos, H. J.; Baccawat-Sikder, K.; Kodadek, T. ChemBiochem 2003, 4,
1242-1245.
(9) Ohlmeyer, M. H.; Swanson, R. N.; Dillard, L. W.; Reader, J. C.; Asouline,
G.; Kobayashi, R.; Wigler, M.; Still, W. C. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 10922-10926.
(10) Blackwell, H. E.; Perez, L.; Stavenger, R. A.; Tallarico, J. A.; Cope-
Eatough, E.; Foley, M. A.; Schreiber, S. L. Chem. Biol. 2001, 8, 1167-
1182.
(11) Clemons, P. A.; Koehler, A. N.; Wagner, B. K.; Sprinings, T. G.; Spring,
D. R.; King, R. W.; Schreiber, S. L.; Foley, M. A. Chem. Biol. 2001, 8,
1183-1195.
(12) Nicolaou, K. C.; Pfefferkorn, J. A.; Mitchell, H. J.; Roecker, A. J.;
Barluenga, S.; Cao, G.-Q.; Affleck, R. L.; Lillig, J. E. J. Am. Chem. Soc.
2000, 122, 9954-9967.
Figure 3. Peptoid array synthesized by digital photolithography. The image
was recorded with excitation at 350 nm and emission at 460 nm. The dark
regions of the array (letters, structure, etc.) represent features on which the
Dabsyl-containing amine was added. The EDANS-containing peptoid
monomer should cover the entire slide. Dabsyl-mediated quenching of
EDANS fluorescence produces the image. Scale in red is added afterward
for illustration purposes.
(13) Scharn, D.; Wenschuh, H.; Reineke, U.; Schneider-Mergener, J.; Germ-
eroth, L. J. Comb. Chem. 2000, 2, 361-369.
(14) Lipshutz, R. J.; Fodor, S. P.; Gingeras, T. R.; Lockhart, D. J. Nat. Genet.
1999, 21, 20-24.
(15) Fodor, S. P.; Read, J. L.; Pirrung, M. C.; Stryer, L.; Lu, A. T.; Solas, D.
Science 1991, 251, 767-773.
(16) Alluri, P. G.; Reddy, M. M.; Baccawat-Sikder, K.; Olivos, H. J.; Kodadek,
T. J. Am. Chem. Soc. 2003, 125, 13995-14004.
coupling of MeNPOC-protected glycolic acid. This was expected
to provide a uniform layer of MeNPOC-protected hydroxyl groups
on the slide. Using digital photolithography,23-26 the MeNPOC groups
were selectively deprotected at specified positions to form a pre-
designed pattern. The slide was then subjected to the four-step cycle
shown in Figure 1B, using the primary amine N-(2-aminoethyl)-
4-[[4-(dimethylamino)phenyl]azo]-benzenesulfonamide (Dabsyl-
amine). Last, the entire slide was irradiated with UV light to remove
all remaining MeNPOC groups. An additional peptoid monomer
was then added using the Figure 1B chemistry, but with the amine
5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid (EDANS).
EDANS and Dabsyl are a pair of molecules that is frequently used
in fluorescent-quenching experiments. The EDANS-containing
monomer should coat the slide uniformly, but its fluorescence
should be quenched at positions where the Dabsyl-containing unit
was constructed in the first cycle of synthesis. As expected, when
the slide was scanned, the image obtained corresponded to that
designed, showing much more intense fluorescence in regions
lacking the Dabsyl-containing monomer (Figure 3).
(17) Figliozzi, G. M.; Goldsmith, R.; Ng, S. C.; Banville, S. C.; Zuckermann,
R. N. Methods Enzymol. 1996, 267, 437-447.
(18) Zuckermann, R. N.; Martin, E. J.; Spellmeyer, D. C.; Stauber, G. B.;
Shoemaker, K. R.; Kerr, J. M.; Figliozzi, G. M.; Goff, D. A.; Siani, M.
A.; Simon, R. J.; Banville, S. C.; Brown, E. G.; Wang, L.; Richter, L. S.;
Moos, W. H. J. Med. Chem. 1994, 37, 2678-2685.
(19) Nguyen, J. T.; Porter, M.; Amoui, M.; Miller, W. T.; Zuckermann, R. N.;
Lim, W. A. Chem. Biol. 2000, 7, 463-473.
(20) Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am.
Chem. Soc. 1992, 114, 10646-10647.
(21) McGall, G. H.; Barone, A. D.; Diggelmann, M.; Fodor, S. P. A.; Gentalen,
E.; Ngo, N. J. Am. Chem. Soc. 1997, 119, 5081-5090.
(22) See Supporting Information.
(23) Traditional photolithographic syntheses of biopolymer libraries on glass
slides, such as oligonucleotides and peptides, require a set of physical
masks. Recently, this process has been revolutionized by the application
of a digital light processor (DLP). UV light can be focused onto a synthesis
chip in any desired pattern by the DLP, eliminating the requirement of
expensive physical masks.
(24) Singh-Gasson, S.; Green, R. D.; Yue, Y.; Nelson, C.; Blattner, F.; Sussman,
M. R.; Cerrina, F. Nat. Biotechnol. 1999, 17, 974-978.
(25) Luebke, K. J.; Balog, R. P.; Mittelman, D.; Garner, H. R. In AdVanced
Microfabricated Sensors; Kordal, R., Usmani, A.M., Law, W.T., Eds.;
American Chemical Society: Washington, DC, 2002.
(26) Balog, R. P.; de Souza, Y. E.; Tang, H. M.; DeMasellis, G. M.; Gao, B.;
Avila, A.; Gaban, D. J.; Mittelman, D.; Minna, J. D.; Luebke, K. J.; Garner,
H. R. Anal. Biochem. 2002, 309, 301-310.
This experiment validates that the chemistry shown in Figure
1B is able to support the creation of a defined array of peptoids.
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