Steven R. Skinner

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The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to(More)
Inhibition of methionine aminopeptidase-2 (MetAP2) represents a novel approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this compound class. Two-step elaboration of fumagillol with amines yielded a diverse series of carbamates at(More)
Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in(More)
The inhibition of protein-protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A(More)
Fumagillin, an irreversible inhibitor of MetAP2, has been shown to potently inhibit growth of malaria parasites in vitro. Here, we demonstrate activity of fumagillin analogs with an improved pharmacokinetic profile against malaria parasites, trypanosomes, and amoebas. A subset of the compounds showed efficacy in a murine malaria model. The observed SAR(More)
An all-optical implementation of a feed-forward artificial neural network is presented that uses self-lensing materials in which the index of refraction is irradiance dependent. Many of these types of material have ultrafast response times and permit both weighted connections and nonlinear neuron processing to be implemented with only thin material layers(More)
We report what is to our knowledge the first observation of fundamental dark spatial solitons. The solitons are launched in bulk semiconductors using an initial condition with odd symmetry. In order to form the initial condition, a glass platelet is positioned in one half of an incident 30-psec pulse, creating a pi phase shift in the spatial profile.(More)
In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this(More)
The optical bench training of an optical feedforward neural network, developed by the authors, is presented. The network uses an optical nonlinear material for neuron processing and a trainable applied optical pattern as the network weights. The nonlinear material, with the applied weight pattern, modulates the phase front of a forward propagating(More)