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Macrocycles1 are generally defined as organic compounds with a ring of at least 12 atoms and hold in a chemical space between small molecules and biologics (Figure 1). With the constrained but somewhat flexible conformation, macrocycles often show higher affinity and selectivity to targets compared with their linear analogues. Therefore, macrocycles constitute an excellent tool for the targets which are difficult to modulate by traditional small molecules. With the enormous structural diversity, many of macrocycles display a wide range of functional capability and remarkable biological activities, which makes them as an important modality in drug discovery. More than 60 macrocycles have been approved as drugs by the U.S. Food and Drug Administration. Most of the macrocyclic drugs are natural products or their derivatives. Infectious disease, oncology, autoimmune disorders, and immunosuppressants are the major therapeutic indications of macrocyclic drugs.

The advancement of DNA Encoded Library (DEL) technology has been significant in recent decades. Beyond its conventional role in small molecule drug discovery, its integration into emerging fields has begun to garner increased interest. This can be attributed to its large chemical space, abundant Structure-Signal Relationship (SSR) data, and inherent DNA conjugation properties. In this context, we will explore alternative applications of DEL technology. It is postulated that with the continuous expansion of the DEL field and technological progression, more applications are yet to be unveiled.

As one of the largest and most functionally diverse gene families, kinases have been recognized as key regulators/mediators of biological signaling networks. More than 30% of drug development efforts target these enzymes in the past two decades. As of January 2024, more than 90 small molecule kinase drugs have been approved by the US Food and Drug Administration (FDA), with approximately 200 orally available protein kinase inhibitors in clinical trials. These compounds have had a significant impact on the treatment of both oncological and non-oncological conditions.

Although many covalent drugs were serendipitously discovered historically, covalent inhibitors were in general discouraged due to the concerns over their interference with biological assays and potential lack of selectivity. Over the past decades, rational design of covalent inhibitors has gained traction and garnered increased interest, particularly due to their stronger potency, prolonged target engagement, increased selectivity, and effectiveness to some drug-resistance mutants to reversible inhibitors.

DNA-encoded library (DEL) technology represents a revolutionary method in drug discovery. Unlike conventional approaches, DEL enables unparalleled exploration of chemical space, leading to the rapid identification of novel potent compounds.

Enzymes are arguably the most ideal targets for small molecule drugs, owing to their involvement in chemical reaction catalysis and the better ligandability of the binding pockets.

Protein-protein interactions (PPI) are physical and chemical contacts between two or more protein molecules. As a fundamental aspect of almost all biological processes, any interference of the sophisticated PPI network could result in potential physiological disorder or disease.

While proteins have traditionally been the primary target class for drug discovery, the landscape is rapidly evolving.

While DNA-encoded library (DEL) selection has been applied to a variety of targets with multiple candidates progressed into different stages of drug development, the utilization of DEL in DNA- and RNA-binding proteins remains questionable. This is largely due to the fact that each DEL compound contains a long stretch of DNA barcode, which when used to screen against DNA- or RNA- binding proteins (transcription factors, DNA polymerases, helicases, DNases, RNases, chromatin modifying complexes, etc.) , would lead to significant false positives.