No abstract

Introduction 4641 1.1. Going in for Protein−Protein Interactions and Pathways 4641 1.2. Protein−Protein Interactions and Small Molecules 4641 2. Case Study 1: Tubulin Polymerization and Natural Product-Derived Small Molecules 4642 3. Case Study 2: p53 and MDM2 Interactions and Small Molecules 4649 3.1. Natural Product Inhibitors of p53−MDM2 Interactions 4650 3.2. β-Hairpin Peptidomimetics 4652 3.3. Terphenyls 4653 3.4. Nutlins 4653 3.5. Benzodiazepines 4654 3.6. Spiro-oxindoles 4656 3.7. Chromenotriazolopyrimidines 4656 3.8. Piperidinones 4657 3.9. Indolo-imidazoles 4658 4. Case Study 3: Modulation of HSP90-Related Protein−Protein Interactions by Natural Products and Related Compounds 4659 4.1. Structure, Conformation, and Functions of HSP 4659 4.2. Hsp90 Inhibitors 4660 5. Case Study 4: Protein−Protein Interactions Centered on the Inhibitors of Apoptosis Proteins (IAPs) and Synthetic Small Molecules 4666 5.1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration–approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [Ki] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (Ki = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (Ki = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets.

Significance Adult hippocampal neurogenesis underpins learning, memory, and mood but diminishes with age and certain illnesses. The orphan nuclear receptor TLX/NR2E1 regulates neural stem and progenitor cell self-renewal and proliferation, but its orphan status has hindered its utilization as a therapeutic target to modulate adult neurogenesis. Here, we deorphanize TLX and report that oleic acid is an endogenous, metabolic ligand of TLX. These findings open avenues for future therapeutic modulation of TLX to counteract cognitive and mental decline in aging and diseases associated with decreased neurogenesis.