Drugging dancing protein clouds: A close look at disorder-based drug design

Abstract

Since it was established in the late 19th century, the traditional “lock-and-key” model of protein functionality has been foundational in biochemistry, particularly with respect to protein structure and function (Fischer, 1894). However, the functionality realm of a protein has evolved, which inevitably rendered the traditional view a rather limited one. Indeed, with the discovery of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs), which do not require a stable structure to function, a paradigm shift was needed more than ever. This is particularly important because IDP and IDR exist as highly dynamic “dancing protein clouds.” Such clouds allow for engagement in diverse interactions that are key to a multitude of biological processes. This dancing cloud concept aptly depicts the notion that proteins are flexible and can change shape over time, akin to a cloud rather than a solid object. As such, our emerging understanding of proteins, particularly the intrinsic disorder thereof, challenges traditional views in biochemistry and the consequent implications for drug design and discovery. It is not surprising then that the roles of IDPs and IDRs in cellular signaling and other regulatory mechanisms are being increasingly appreciated and are fundamentally resha** our comprehension of the long-standing “key and lock” protein functionality. Uversky (2025) provides an extensive and critical look at the ever-growing field of targeting disordered proteins. The author pays close attention to the tractability and druggability of these IDPs (and IDRs). Not only does his paper effectively appraise the uniqueness of these entities as desirable pharmacological targets, but it also provides ample discussion of various modalities for targeting them. The author aptly discusses how in spite of, or in some instances because of, their interesting particularities, IDPs and IDRs are nonetheless druggable (Uversky, 2025). Uversky highlights that IDPs, ubiquitous in eukaryotic cells, have several advantages, including being flexible structures, which lends them multifunctionality. In addition, their binding dynamics/fuzziness, including decoupling specificity and affinity of binding, allow for weak yet specific complexes that are critical for signaling repression or deactivation. Other distinctive features include faster kinetics of interaction and conformational pliability, as well as oneto-many and many-to-one interactions. A rather interesting feature of some IDPs/IDRs is that their functions may be elicited despite, or even originate by virtue of, the lack of a thermodynamically very stable structure in a protein molecule or motif. The paper discusses various potential applications of IDP-based drug delivery systems. These include chimeric polypeptides fused