<p>We are excited to share this special issue dedicated to Jeffery Kelly, commemorating his 2023 Wolf Prize in Chemistry. This award recognizes his pioneering research accomplishments, which have dramatically changed our fundamental understanding of how proteins (mis)fold in vitro and in vivo while at the same time leveraging those discoveries to change the lives of patients across the globe. The award specifically refers to the latter: “for developing a clinical strategy to ameliorate pathological protein aggregation”. This is exemplified by the development of Tafamidis,<span><sup>1</sup></span> the first clinically approved molecule to treat a disease of protein misfolding.<span><sup>2, 3</sup></span></p><p>Jeff's discovery that protein misfolding of transthyretin (TTR) is an obligate step prior to protein aggregation<span><sup>4</sup></span> established that preventing the accumulation of misfolded proteins can block disease pathology. Rigorous biochemical and biophysical characterization established that transthyretin tetramer dissociation into monomers is the rate-limiting step that initiates protein misfolding.<span><sup>5</sup></span> This critical insight motivated the development of small molecules that could stabilize the native conformation of TTR,<span><sup>6</sup></span> culminating in the development and clinical approval of Tafamidis.</p><p>Later, Jeff and his collaborators introduced the idea of protein homeostasis (or proteostasis).<span><sup>7</sup></span> Protein folding and maturation into its native structure is not only governed by the intrinsic stability of each polypeptide chain, but in a cellular environment, the large ensemble of molecular chaperones, co-chaperones, other protein quality factors, and their interacting activities maintain the integrity of the proteome for cellular and organismal health. Importantly, dysregulation of the proteostasis network can lead to insufficient protein folding capacity and accumulation of misfolded proteins, which is associated with various disease states, ranging from neurodegeneration to diabetes and cancer.<span><sup>8, 9</sup></span></p><p>Several reviews and articles in this special issue address how a detailed understanding of protein misfolding and the proteostasis network can be leveraged in therapeutic development. These contributions highlight the impact that Jeff's work has had on the broader chemistry and biology research community.</p><p>Although transthyretin amyloidosis was once thought to be rare, we now know that millions of people are carriers of likely pathogenic variants.<span><sup>10</sup></span> Following the success of Tafamidis, there are now many emerging approaches for therapeutic intervention in this disease class, as reviewed by Per Hammarström in this issue.<span><sup>11</sup></span> Another class of protein associated with systemic amyloidosis is immunoglobulin light chain, which lead to AL amyloidosis. Gareth Morgan reviews how both amyloidogenicity and
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The cover art depicts Jeffery Kelly's pioneering development of Tafamidis as a clinical strategy to ameliorate transthyretin protein aggregation (in the center). Surrounding images highlight examples from this special issue of how his work has influenced other approaches to characterize and target the etiology of diverse protein misfolding diseases.