Authors:

Jocelyn Yang

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About Paper:

DNA-encoded libraries (DELs) are a new technology used for drug discovery. Contrary to traditional methods which synthesize and test each molecule separately, the encoding aspect of DELs enables both pooled chemical reactions for simultaneous synthesis and screening of a drug candidate library. This approach greatly improves the efficiency of the drug discovery process. In DEL preparation, each molecule is attached to a unique DNA tag. However, DEL-compatible reactions are often limited due to DNA damage. Reductive alkylation of amines on DNA is one of the most robust and non-damaging reactions; however, the required aldehyde building blocks have limited commercial availability due to degradation upon storage. To address this, a series of functional group conversion reactions for aldehyde synthesis were investigated for their potential usage in DEL reactions. Carboxylic acids, alcohols, and amines were first converted to aldehydes in an off-DNA reaction, then reacted with DNA by reductive amination directly from the crude reaction. The DNA reaction yields were quantified with liquid chromatography-mass spectrometry (LC-MS). The integration of a peak on the LC-MS with a mass of the desired product showed that an aldehyde made by oxidation of an alcohol with 2-iodoxybenzoic acid (IBX) had the ability to react onto DNA. After testing various conditions, the highest yield (>70%) was obtained using 500 mM MES buffer. Combining this reaction with existing ones increases the molecular diversity, raising the probability of finding a drug candidate. Future applications include constructing DELs with these reactions to test their efficacy and diversity in DEL synthesis. Keywords: Biochemistry; Chemistry; Drug Discovery; DNA-Encoded Libraries; Combinatorial Chemistry

Source:

Purdue University / 2025

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Co-authors:

Jocelyn Yang