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Kinetic target-guided synthesis represents an efficient hit-identification strategy, in which the protein assembles its own inhibitors from a pool of complementary building blocks via an irreversible reaction. Herein, we pioneered an in situ Ugi reaction for the identification of novel inhibitors of a model enzyme and binders for an important drug target, namely, the aspartic protease endothiapepsin and the bacterial β-sliding clamp DnaN, respectively. Highly sensitive mass-spectrometry methods enabled monitoring of the protein-templated reaction of four complementary reaction partners, which occurred in a background-free manner for endothiapepsin or with a clear amplification of two binders in the presence of DnaN. The Ugi products we identified show low micromolar activity on endothiapepsin or moderate affinity for the β-sliding clamp. We succeeded in expanding the portfolio of chemical reactions and biological targets and demonstrated the efficiency and sensitivity of this approach, which can find application on any drug target., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies ( i.e. , cancer and neurodegeneration) have highlighted their potential as therapeutic targets. In this scenario, Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs have been gaining growing attention. Compounds able to modulate the complex stability could constitute an innovative pharmacological strategy for the treatment of numerous diseases. Nevertheless, medicinal-chemistry efforts aimed at developing such compounds are still at an early stage. As part of our ongoing research in this field, we hereby present the rational design and synthesis of structurally novel HuR ligands, potentially acting as HuR-RNA interferers. The following assessment of the structural features of their interaction with HuR, combining saturation-transfer difference NMR and in silico studies, provides a guide for further research on the development of new effective interfering compounds of the HuR-RNA complex., Competing Interests: The authors declare no competing financial interest.

Kinetic target-guided synthesis (KTGS) is a powerful strategy in which the biological target selects its own inhibitors by assembling them from biocompatible reagents via an irreversible process. In this approach, the biological target accelerates the reaction between complementary building blocks by bringing them in close proximity and proper orientation. KTGS has found application on various targets. Herein, we performed a druggability assessment for each target family reported in KTGS, calculated the pocket properties, and used them to extract possible discriminating factors for successful KTGS studies. A trend for less enclosed pockets emerged, but overall we conclude that the KTGS approach is universal and could be used without restrictions regarding the physicochemical properties of the addressed pocket.

Acylhydrazone-based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone-based inhibitors of the aspartic protease endothiapepsin as a follow-up to a DCC study. The most successful bioisostere is equipotent, bears an amide linker, and we confirmed its binding mode by X-ray crystallography. Having some validated bioisosteres of acylhydrazones readily available might accelerate hit-to-lead optimization in future acylhydrazone-based DCC projects., (© 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Post-transcriptional processes have been recognised as pivotal in the control of gene expression, and impairments in RNA processing are reported in several pathologies (i.e., cancer and neurodegeneration). Focusing on RNA-binding proteins (RBPs), the involvement of Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs in the aetiology of various dysfunctions, has suggested the great potential of compounds able to interfere with the complex stability as an innovative pharmacological strategy for the treatment of numerous diseases. Here, we present a rational follow-up investigation of the interaction between ELAV isoform HuR and structurally-related compounds (i.e., flavonoids and coumarins), naturally decorated with different functional groups, by means of STD-NMR and Molecular Modelling. Our results represent the foundation for the development of potent and selective ligands able to interfere with ELAV-RNA complexes.

RNA-binding proteins play a key role in post-transcriptional processes. Among these proteins, embryonic lethal abnormal vision (ELAV) proteins are among the best described. ELAV proteins predominantly act as positive regulators of gene expression, and their dysregulation is involved in several pathologies, such as cancer, inflammation, and neurodegenerative diseases. Only a few structurally unrelated compounds interfering with ELAV protein-mRNA complexes have been identified by applying high-throughput screening approaches. Considering the structural diversity of the compounds discovered so far and the different techniques employed for screening their ability to interfere with ELAV protein-mRNA complexes, drawing conclusions from structure-activity relationships remains a challenge. We performed docking studies to understand the interactions of compounds reported over the past decade to be inhibitors of ELAV proteins and to evaluate the potential of computer-aided drug design to target this family of proteins for further drug discovery.

Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure-based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co-activator recruitment. We solved the crystal structure of the spiroketal-hRXRα-TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co-crystal structure, the first of a designed spiroketal-protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes., (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

There is an urgent need for the development of efficient methodologies that accelerate drug discovery. We demonstrate that the strategic combination of fragment linking/optimization and protein-templated click chemistry is an efficient and powerful method that accelerates the hit-identification process for the aspartic protease endothiapepsin. The best binder, which inhibits endothiapepsin with an IC 50 value of 43 μm, represents the first example of triazole-based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

We report a new family of chiral bifunctional acid/base type organocatalysts, 2-aminoDMAP/Squaramides, which are proved to be highly active (1 mol % cat. loading) promoters in conjugate addition of dibenzoylmethane to various trans-β-nitroalkenes. Steric demand of the catalysts was clearly seen by a set-by-set modulation of the squaramide unit through electronic and steric factors. The synergistic cooperation of 2-aminoDMAP “superbase” and sterically encumbered squaramide (H-bond donor) enabled complete conversion of a range of reactants into corresponding Michael adducts in a couple of hours with exquisite selectivities (up to 98% ee).