High-throughput sequencing allows the identification of binding molecules isolated from DNA-encoded chemical libraries

doi:10.1073/pnas.0805130105

High-throughput sequencing allows the identification of binding molecules isolated from DNA-encoded chemical libraries

^aInstitut für Pharmazeutische Wissenschaften Departement für Chemie und Angewandte Biowissenschaften, Eidgenössische Technische Hochschule, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland;
^bIstituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Via Fratelli Cervi 93, 20090 Segrate Milan, Italy; and
^cPhilochem AG, c/o Eidgenössische Technische Hochschule, Wolfgang-Pauli-Strasse 10 CH-8093 Zurich, Switzerland

Edited by Jonathan A. Ellman, University of California, Berkeley, CA, and accepted by the Editorial Board September 9, 2008 (received for review May 29, 2008)

Abstract

DNA encoding facilitates the construction and screening of large chemical libraries. Here, we describe general strategies for the stepwise coupling of coding DNA fragments to nascent organic molecules throughout individual reaction steps as well as the first implementation of high-throughput sequencing for the identification and relative quantification of the library members. The methodology was exemplified in the construction of a DNA-encoded chemical library containing 4,000 compounds and in the discovery of binders to streptavidin, matrix metalloproteinase 3, and polyclonal human IgG.

Footnotes

¹To whom correspondence should be addressed. E-mail: dario.neri{at}pharma.ethz.ch
Author contributions: L.M. and D.N. designed research; L.M., Y.Z., J.S., M.L., and S.M. performed research; L.M., Y.Z., J.S., M.L., G.D.B., E.R., C.D., and S.M. contributed new reagents/analytic tools; L.M., Y.Z., M.L., C.D., and S.M. analyzed data; and D.N. wrote the paper.
Conflict of interest statement: The IgG binders described in this article have been patented by Philochem, a spin-off company of ETHZurich of which D.N. owns shares.
This article is a PNAS Direct Submission. J.A.E. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/cgi/content/full/0805130105/DCSupplemental.
Freely available online through the PNAS open access option.