Aberrant apoptosis can lead to acute or chronic degenerative diseases. Mitochondrial outer membrane permeabilization (MOMP) triggered by the oligomerization of the Bcl-2 family proteins Bax/Bak is an irreversible step leading to execution of apoptosis. Here, we describe the discovery of small-molecule inhibitors of Bax/Bak oligomerization that prevent MOMP. We demonstrate that these molecules disrupt multiple, but not all, interactions between Bax dimer interfaces thereby interfering with the formation of higher-order oligomers in the MOM, but not recruitment of Bax to the MOM. Small-molecule inhibition of Bax/Bak oligomerization allowed cells to evade apoptotic stimuli and rescued neurons from death after excitotoxicity, demonstrating that oligomerization of Bax is essential for MOMP. Our discovery of small-molecule Bax/Bak inhibitors provides novel tools for the investigation of the mechanisms leading to MOMP and will ultimately facilitate development of compounds inhibiting Bax/Bak in acute and chronic degenerative diseases.

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.

The recent emergence of highly transmissible SARS-CoV-2 variants illustrates the urgent need to better understand the molecular details of the virus binding to its host cell and to develop anti-viral strategies. While many studies focused on the role of the angiotensin-converting enzyme 2 receptor in the infection, others suggest the important role of cell attachment factors such as glycans. Here, we use atomic force microscopy to study these early binding events with the focus on the role of sialic acids (SA). We show that SARS-CoV-2 binds specifically to 9-O-acetylated-SA with a moderate affinity, supporting its role as an attachment factor during virus landing to cell host surfaces. For therapeutic purposes and based on this finding, we have designed novel blocking molecules with various topologies and carrying a controlled number of SA residues, enhancing affinity through a multivalent effect. Inhibition assays show that the AcSA-derived glycoclusters are potent inhibitors of cell binding and infectivity, offering new perspectives in the treatment of SARS-CoV-2 infection.