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Combinatorial Chemistry

Overview

PharmaSeq has developed an innovative platform for “next-generation combinatorial chemistry.” Combinatorial libraries, with their enormous diversity, have the potential to resolve the complexity of identifying biomarkers against high background protein levels, yet they have fallen out of favor due to difficulties with indexing individual particles. PharmaSeq’s platform resolves this problem by providing a means to identify the peptide sequence of each molecule: by its association with the ID number of the p-Chip on which it is synthesized.

Moreover, the ability to sort p-Chips according to their ID allows for unprecedented sequence-directed combinatorial synthesis of peptides and oligonucleotides (under development). Here, an organic molecule having a predetermined sequence or structure can be synthesized on a p-Chip having a predefined ID. This eliminates to a large degree unnecessary syntheses of random combinations of chemical building blocks which occur in a typical combinatorial chemistry approach.

PharmaSeq’s system features ultra-small (500 x 500 x 100 μm), laser-light-powered microtransponders called p-Chips. Each p-Chip has a unique serial ID number that is read at each split step of the split-and-mix method of peptide synthesis. This technology enables, for the first time, a true indexed and immediately decodable one-particle-one-compound (OPOC) library, providing prompt recognition of differential binding patterns.

This technology has already been gaining traction. For example, PharmaSeq and its collaborators at the Yale University School of Medicine are creating a p-Chip-encoded combinatorial peptide library appropriate for identification of auto-antibodies to tumor-associated antigens (TAAs).

By dramatically streamlining the overall process required to identify multiple biomarkers, a p-Chip library has the sensitivity, reliability and ease-of-use required to substantially improve the potential for drug discovery (e.g., cancer receptors), protein characterization and quality control of predicting biological therapeutics (e.g., antibodies).

For a quote, contact us at info@pharmaseq.com or (732) 355-0100. We will be happy to discuss your specific needs and provide an estimate.

The p-Chip System for Creating Peptide Libraries

PharmaSeq’s system for creating peptide libraries consists of p-Chips, the Simuplex flow reader, the spin reader for reading p-Chip IDs, a peptide synthesizer (user-provided), a high-speed/precision sorter for p-Chips (under development) and software. Each p-Chip is a very small, unitary integrated circuit that can transmit its ID via radio frequency when stimulated by a pulsed laser light. It is composed of photocells, a complete electronic circuit, an antenna and a 30-bit memory, allowing for over 1.1 billion unique ID codes. The p-Chip’s surface is made of silicon dioxide, and methods to stably coat the p-Chip with aminosilane compounds are well-established. p-Chips are highly stable in most aqueous solutions and organic solvents tested and have excellent temperature stability.

PharmaSeq’s system uses the optimal solid-phase peptide synthesis (SPPS) method to synthesize peptide libraries of 4,000-10,000 p-Chips each, or larger. From the combinatorial library synthesis phase the p-Chip system proceeds seamlessly to the screening and data analysis phase. In this phase, binding patterns to the receptor, biomarker or target protein are immediately identified based on the ID number readout of the chip in a high-speed flow reader, the Simuplex. The Simuplex flow reader is similar to a flow cytometer in that fluorescent signals are detected from particles (in this case p-Chips) when they are excited by laser light. The peptide library is evaluated using existing software, which classifies peptide/p-Chip “hits” according to their sequence and the binding propensity to the target.

Key Points

PharmaSeq’s p-Chip system provides an electronically-encoded approach to high-throughput screening of complex biological samples. The major advantage of the p-Chip system for combinatorial chemistry is its one-particle-one-compound indexing capability: each peptide is linked to the ID of the p-Chip on which it is synthesized. p-Chips are highly stable in most aqueous solutions and organic solvents tested and have excellent temperature stability.

Links

SIMUPLEX-COMBI INSTRUMENT FOR SCREENING/ASSAYSSIMUPLEX-COMBI INSTRUMENT FOR SCREENING/ASSAYS