Drug Discovery : Libraries


Library of Glycosylated Chlorambucil Analogs for Cancer Treatment

UW–Madison researchers have used glycorandomization to develop a set of 63 glycosylated chlorambucil molecules. Several of these novel compounds are efficacious against various types of cancer cells. They could be developed into cancer therapeutics.

Novel Glycosyltransferases and Improved Methods of Creating Glycosylated Nucleotides for Drug Discovery

UW–Madison researchers have developed novel glycosyltransferases and improved methods of synthesizing NDP-sugars.  The methods exploit the reversibility of glycosyltransferases to rapidly generate exotic NDP-sugars.  These nucleotides are a starting material in the generation of glycosylated drug compounds using the glycorandomization methodology. 

The researchers discovered that in addition to transferring sugar groups from an NDP-sugar to another molecule, glycosyltransferases can catalyze the removal of sugars from glycosylated natural products and the transfer of a sugar from one natural product backbone to a different natural product backbone, thus allowing sugars and aglycons to be exchanged with ease.

Novel Antibacterial Small Molecules

UW-Madison researchers have developed a versatile platform for screening compounds for antibacterial activity, along with new antibacterial agents that are effective against Gram-positive bacteria like methicillin-resistant S. aureus. The researchers used combinatorial synthesis methods to generate macroarrays comprising a library of chalcone-based small candidate molecules. These macroarrays use a Rink amide linker to attach the small molecules to a solid support. This allows additional chemical moieties to be covalently attached to the small molecules, further enhancing the diversity of the molecules that can be synthesized and screened. The Rink linker also results in the formation of an amide group on the small molecules that are released from the support, enhancing their water solubility and potentially their biological activity.

The resulting compound library was screened for antibacterial activity using an overlay technique, and the minimal inhibitory concentrations (MICs) of select compounds were quantified. Several antibacterial compounds were identified, including chalcone and chalcone derivatives such as alkylpyrimidine, aminopyrimidine and cyanopyridine. These compounds could be used to treat patients infected with bacteria, including drug resistant bacteria, and could also be used for sterilization and disinfection.

Improved Phage Display System Enables Screening of Liver-Specific Peptides

UW–Madison researchers have developed a phage display system that utilizes the p17 tail protein of the T7 virus as the fusion target for expressing a library of peptides.  These peptides may include peptides useful for targeting and internalizing the phage into specific cells such as liver cells.  In addition to screening for liver-targeting peptides, the display system can be used to identify ligands with high binding affinities or establish pharmacophores useful in rational drug design.

Type 1 Polyketide Synthase Extender Units

UW-Madison researchers have discovered two novel extender units that can be used in the creation of new polyketide derivatives. This invention also includes the enzymes needed to form the extender units and the PKSs needed to incorporate the units into the polyketide backbone.

One or both of the extender units can be introduced into a desired polyketide to create new structural derivatives. For example, the PKSs involved in the production of polyketides such as erythromycin, rifamycin, rapamycin, FK520 or zwittermicin can be engineered to incorporate these units. The resulting polyketide derivatives can then be used as bioactive molecules or as lead compounds for further modification.

Neoglycorandomization and Digitoxin Analogs

UW-Madison researchers have now developed a different approach to glycosylating natural compounds to create a large library of diverse compounds for high throughput screening. This approach, neoglycorandomization, uses a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation. It is based on the chemoselective formation of glycosidic bonds between the reducing sugars and an aglycon with a secondary alkoxyamine.

To form a neoglycoside, the alkoxyamine-containing aglycon is reacted with at least one reducing sugar selected from the group consisting of L-sugars, D-sugars, amino-sugars, deoxy-sugars, dideoxy-sugars, glucose epimers, substituted sugars, uronic acids, and oligosaccharides.

Diazaphosphacycles, Which Are Used to Catalyze Commercially Important Reactions, and Methods of Synthesis

UW–Madison researchers have developed diazaphosphacycles and methods for synthesizing them. They further developed transition metal complexes that include diazaphosphacycles and methods for using them in catalytic transformations. The method to synthesize a diazaphosphacycle includes reacting a phosphine with a diimine and optionally one or more equivalents of an acid halide, a sulfonyl halide, a phosphoryl halide or an acid anhydride in the substantial absence of O2 to form the diazaphosphacycle. The phosphine has the formula R1-PH2, where R1 is a substituted or unsubstituted aryl, alkyl, alkenyl, cycloalkyl or ferrocenyl group.

Use of Glycorandomization to Produce Novel Glycosylated Products for Drug Discovery

A UW-Madison researcher has developed combinatorial methods for rapidly generating a diverse library of novel glycosylated compounds for use in drug discovery. Glycorandomization is a chemoenzymatic strategy that overcomes the limitations in natural product derivatization associated with both chemistry-based approaches and in vivo engineering.

In the methods, at least one aglycon and a pool of nucleoside diphosphate (NDP)-sugars are incubated with a glycosyltransferase enzyme to produce glycorandomized structures. The pool of NDP-sugars may include difficult-to-produce or never-before-produced sugars, which can now be made easily and efficiently through a one-step nucleotidyltransferase-catalyzed conversion developed by the inventors. The glycorandomized structures may be incubated with the sugars and glycosyltransferase multiple times to generate additional compounds. The glycorandomized structures may also be incubated with at least one chemoselectively ligatable moiety to generate chemoselectively-ligated compounds.

One-Step Synthesis of Diazaphosphacycles

UW-Madison researchers have developed a relatively easy, one-step method of synthesizing a diazaphosphacycle. To generate a diazaphosphacycle, a phosphine is reacted with a diimine and one or more equivalents of an acid halide, a sulfonyl halide, a phosphoryl halide, or an acid anhydride, in the absence of oxygen. The phosphine has the formula R1-PH2, where R1 is a substituted or unsubstituted aryl, alkyl, alkenyl, cycloalkyl or ferrocenyl group.

Increasing Secondary Metabolite Production in Fungus for Drug Development

The researchers now have developed a set of genetically modified Aspergillus nidulans strains with increased secondary metabolite production. The strains overexpress one or both of the global regulators previously implicated in secondary metabolite production. Moreover, naturally occurring gene clusters in the strains are deleted to reduce competition for the desired genes.