Self-assembled Libraries

A new trio-pharmacophore self-assembly DNA-encoded chemical library (T-DEL) comprising 883 x 30 x 890 members was assembled, validated and used for  the y de novo identifications of µM inhibitors of matrix metalloprotease-2 and −9. In this report a trio-pharmacophore DNA-encoded self-assembling chemical library (T-DEL) is generated by the DNA-hybridization of two single-strand DNA-encoded sub-libraries (SL) A and C on a third … Read more

A 10,000-member DNA-encoded dynamic library was selected against sirtuin-1, 2, and 5 (SIRT1, 2, 5) and the BD1 and BD2 of bromodomain 4 (BRD4), respectively. DNA-encoded dynamic libraries are self-assembled libraries comprising DNA strands with short hybridization site (e.g. ,6–7 bases), so that the duplexes are “dynamic” (i.e., unstable) and they rapidly exchange DNA strands, thereby forming in-situ combinatorial library of fragment pairs. The … Read more

A dual Bcl-XL / Bcl-2 low nM range binder was discovered from a PNA-encoded library following DNA-microarray screening. Cell viability assays revealed EC50 value of 1.7 μM against lymphocyte cell line derived from a leukemia patient. PNA-encoded libraries are typically synthesized by traditional solid-phase peptide synthesis (SPPS) in “split-&-pool” fashion. The PNA chemical stability makes the synthesis of very diverse “DNA-like” conjugate libraries … Read more

Orthogonal screening of Encoded Self-Assembly Chemical (ESAC) libraries enabled the lead optimization of 4,5-Dihydrobenzodiazepinone ring (THBD)-based ligands, a known selective inhibitor of CREB-binding protein (CREBBP) bromodomain, and the identification of a new pair of fragments with a submicromolar affinity for the CREBBP bromodomain.   CREB-binding protein (CREBBP) bromodomain presents two adjacent binding pockets, thus representing an ideal protein target for Encoded Self-Assembly Chemical (ESAC) … Read more

A 10,000-member DNA-encoded dynamic library has been synthesized and used to identify potent and specific bivalent sirtuin-3 (SIRT3) low micromolar inhibitors. In this report, a DNA-encoded dynamic library (DEDL) has been combinatorially self-assembled by mixing two HPLC purified DNA-conjugated sub-libraries, each containing 100 compound members. Following incubation of the DEDL library with six different unmodified target protein of interest (including streptavidin, ER-alpha, SIRT3, SAE1, UBC9 and TRIM28) and DNA-double strand photo-cross linking, … Read more

Selections performed against JNK1 through an encoded self-assembling chemical library comprising 148’135 members (559×265 compounds) allowed the identification of a specific ligand capable of selectively modifying the catalytic site by Michael addition reaction.  Philochem in collaboration with ETH Zurich, the Institute of Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University (Germany) and the Structural Genomics Consortium and Target Discovery Institute, … Read more

DNA/PNA-encoded hybrid libraries tandem DNA-conjugate “affinity maturation” libraries to isolate nM PTP1B selective inhibitors. DNA display of PNA-encoded libraries was used to isolate fragments containing various phosphotyrosine surrogates with diverse triazoles. Panning on prototypical phosphatase (PTP1B) and microarray-based decoding of the hybrid self-assembled combinatorial library (comprising 62,500 fragment combinations) allowed the identification of several lead-fragments. A subsequent focused DNA-conjugate “affinity … Read more

The group of Prof. Neri at ETH Zurich in collaboration with Philochem described the construction and high-througput sequencing decoding of an ESAC-duplex library comprising 111.100 compounds. The implemention of a novel encoding strategy, which transfer the sequence information from one strand to the complementary one, allowed the identification of synergistic binding pairs. In particular, the authors reported the de novo isolation of … Read more

The group of Prof. Winssinger (NCCR Chemical Biology, University of Geneva) reported the use of a self-assembling DNA/PNA-hybrid encoded libraries comprising 65.000 compounds to identify synergistically binding pharmacophores to Hsp70.  As the identification of an appropriate linker to covalently pair the fragments is in general a cumbersome trial-and-error task, the information obtained from the fragment screen were employed as … Read more

In 2011 for the first time, using a PNA/DNA self-assembling approach, Winssinger and co-workers at ISIS Strasbourg synthesized a 37.485 member carbohydrate DNA-encoded library containing consensus sequences for DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin), a protein involved in the initial stages of the human immunodeficiency virus infection. After selection, SPR (Surface Plasmon Resonance) revealed for the best … Read more