Exploring Protein Folding Intermediates Across Physiology and Therapy

In recent years, advancements in computational methodologies have shed light on the complex process that makes proteins fold into their three-dimensional shapes. These new tools have helped us understand the steps proteins take to achieve these structures, revealing the presence of metastable intermediates along the folding pathways. This newfound understanding has led to the development of a novel drug discovery strategy known as Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT). This approach specifically targets folding intermediates to modulate protein expression levels, thus opening new opportunities for pharmacological intervention. This approach could be particularly relevant for diseases linked to targets that were previously considered "undruggable." A promising outcome of the PPI-FIT strategy is the identification of SM875, a compound that has been shown to lower prion protein (PrP) levels, positioning it as a potential therapeutic candidate for prion diseases. This study describes the initial phase of optimization of the SM875 scaffold. It encompasses the chemical diversification of SM875, followed by systematic evaluations of its biological activity and toxicity, with the aim of establishing structure-activity relationships (SAR). This knowledge is instrumental in guiding the synthesis of analogs with enhanced properties, advancing them through the development pipeline toward clinical application. Furthermore, this work investigates the potential regulatory function of folding intermediates in physiological processes, hypothesizing that they may serve as substrates for post translational modifications (PTMs). This hypothesis proposes an expansion of the current paradigm, suggesting that folding intermediates could constitute an additional layer of regulation within the complex network of proteostasis.