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The original version of this Article contained a factual error within the discussion section, which incorrectly stated that SARS-CoV-2 expresses a hemagglutinin esterase. This has been corrected in the PDF and HTML version of the Article by the removal of the corresponding text. The deleted text is reproduced below: Besides the spike glycoprotein, coronaviruses, including SARS-CoV-2, express at their surface the hemagglutinin esterase (HE) that often contains an active lectin domain that mediates glycan binding in several other viruses. However, the HE lectin domains of HCoV-OC43 and HCoV-HKU1 lost their glycan binding capacity due to mutations and deletion during adaptation to human host62. Our result also suggests that HE might not be directly involved in 9-AcSA binding, as binding kinetics to AcSA is similar on purified S1 and at the virion level. However, as their esterase activity is maintained, HE could be involved in the deacetylation during release of viral progeny from the host cell surface and possibly also for breaking decoy interactions of the S protein with O-AcSA carrying mucins63.

Significance SARS-CoV-2 has had a crippling impact on human life globally. Vaccine development has been used as a first-line strategy for COVID-19 prevention and mitigation; however, small-molecule drugs are still vitally needed to extend treatment options. Traditional screening methods for identifying biologically active small molecules are sluggish and often sample an insufficient number of compounds to identify suitable hits. Here, we applied a screening method known as DNA-encoded chemistry technology (DEC-Tec) to screen billions of compounds against a critical viral protein, Mpro. In rapid fashion, we identified the compound CDD-1713 as a potent and selective Mpro inhibitor. This study illuminates DEC-Tec as a highly expeditious strategy toward generating small molecules against critical targets of infectious agents., 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.

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 [K i] = 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 (K i = 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 (K i = 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.

International audience; Pseudomonas aeruginosa is a human pathogen belonging to the top priorities for the discovery of new therapeutic solutions. Its propensity to generate biofilms strongly complicates the treatments required to cure P. aeruginosa infections. Herein we describe the synthesis of a series of novel rotaxanes comprised of a central galactosylated pillar [5]arene, a tetrafucosylated dendron and a tetra-guanidinium subunit. Strategically, we exploited a supramolecular assembly technology to generate complex rotaxanes from relatively simple subcomponents. The final glycorotaxanes displayed high affinity for the two P. aeruginosa lectins LecA and LecB as evaluated by Isothermal Titration Calorimetry. Potent inhibition levels of P. aeruginosa biofilm growth were evidenced showing that the three subunits of the glycorotaxanes work synergistically. Such antibiofilm potency had rarely been reached in the literature. Importantly, none of the final rotaxanes was bactericidal, showing that their antibiofilm activity is lectinmediated but does not depend on bacteria killing, which is a rare feature for antibiofilm agents.

It is assumed that intracellular pathogenic bacteria have to cope with DNA alkylating stress within host cells. Here we use single-cell reporter systems to show that the pathogen Brucella abortus does encounter alkylating stress during the first hours of macrophage infection. Genes encoding direct repair and base-excision repair pathways are required by B. abortus to face this stress in vitro and in a mouse infection model. Among these genes, ogt is found to be under the control of the conserved cell-cycle transcription factor GcrA. Our results highlight that the control of DNA repair in B. abortus displays distinct features that are not present in model organisms such as Escherichia coli., SCOPUS: ar.j, info:eu-repo/semantics/published

Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds.

A practical stereoselective synthesis to obtain the substituted furan ring as the substructure of eribulin is developed. An asymmetric syn-aldol and intramolecular oxy-Michael were two key steps in our approach. The functionalized furan derivatives were then utilized further to build the 14- and 12-membered macrocyclic diversity as trans- and cis-fused (C-29 and C-30) compounds. This is the first report of building a chemical toolbox with macrocyclic small molecules having trans- or cis-fused 14- or 12-membered rings containing the substructure of eribulin and its diastereomer.

A stereoselective synthesis of a rapamycin fragment is developed and further utilized toward building a macrocyclic chemical toolbox. The amino alcohol moiety embedded in the 22-membered macrocyclic ring allowed for the addition of a variation in the chiral side chain. The key reactions leading to the synthesis of the rapamycin-derived pyran fragment include the following: (i) Paterson aldol, (ii) stereoselective β-OH carbonyl reduction, and (iii) regio- and stereoselective intramolecular oxy-Michael reaction. The other piece needed for building the macrocyclic diversity was obtained from the coupling of various amino alcohol moieties with S-pipecolic acid.

Mitochondria produce the majority of cellular energy through the process of oxidative phosphorylation and play a central role in regulating the functionality and survival of eukaryotic cells. Under physiological stress, mitochondrial membrane permeabilization results in the release of apoptogenic material such as cytochrome c in the cytoplasm, which thereby initiates caspase activation and the consequent cell death. In our present study, we screened a series of compounds for their ability to inhibit mitochondrial membrane permeabilization and to prevent cytochrome c release during the endoplasmic reticulum stress in cultured pancreatic β-cells. Three benzofuran-based macrocyclic small molecules, that is, 2.4c, c104, and c108, were found to restore the depolarization of mitochondrial membrane potential and to prevent the release of cytochrome c from mitochondria. Interestingly, the acyclic precursor of 2.4c (i.e., 2.3c) did not show any effect, whereas the macrocyclic derivative obtained by utilizing ring-closing metathesis as the “stitching technology” led to this function. The macrocyclic architecture seems to play a crucial role in presenting various functional moieties in the right orientation to observe this effect.

Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds.

1.. Introduction B 1.1. Going in for Protein−Protein Interactions and Pathways B 1.2. Protein−Protein Interactions and Small Molecules B 2. Case Study 1: Tubulin Polymerization and Natural Product-Derived Small Molecules C 3. Case Study 2: p53 and MDM2 Interactions and Small Molecules J 3.1. Natural Product Inhibitors of p53−MDM2 Interactions K 3.2. β-Hairpin Peptidomimetics M 3.3. Terphenyls N 3.4. Nutlins N 3.5. Benzodiazepines O 3.6. Spiro-oxindoles Q 3.7. Chromenotriazolopyrimidines Q 3.8. Piperidinones R 3.9. Indolo-imidazoles S 4. Case Study 3: Modulation of HSP90-Related Protein−Protein Interactions by Natural Products and Related Compounds T 4.1. Structure, Conformation, and Functions of HSP T 4.2. Hsp90 Inhibitors U 5. Case Study 4: Protein−Protein Interactions Centered on the Inhibitors of Apoptosis Proteins (IAPs) and Synthetic Small Molecules AA 5.1. Overview of Functions of IAPs AA 5.2. Death Receptor Pathway of Caspase Activation AB 5.3. Mitochondrial Pathway of Caspase Activation AB 5.4. Converging Points and Cross-Talk AB 5.5. Nonpeptidic Small Molecules AC 5.5.1. TWX Molecules: First Reported Nonpeptide Inhibitor of XIAP (BIR2 domain) AC 5.5.2. Polyphenylureas: Another Class of Nonpeptide Inhibitors of XIAP (BIR2 domain) AC 5.6. Monovalent SMAC Mimetics AC 5.6.1. Conformationally Constrained Monovalent SMAC Mimetics AC 5.6.2. Isostere Design Using [7,5]-Bicyclic Scaffold AD 5.6.3. Design and Synthesis of Azabicyclooctane Scaffold-Based SMAC Mimetics AE 5.6.4. Some More Monovalent SMAC Mimetics AE 5.6.5. Diazabicyclic Scaffold-Based Peptide Mimetics AE 5.7. Bivalent SMAC Mimetics: Design and Synthesis AF 5.7.1. Unexpected Discovery of First Bivalent SMAC Mimetic AF 5.7.2. Bivalent Small Molecules Based on Monovalent SMAC Mimetics AF 6. Case Study 5: Bcl-2 Protein Family and Synthetic Small Molecules AG 6.1. BCL-2 Protein: Mitochondrial Permeabilization in Apoptosis AI 6.2. Peptides and Peptidomimetics AJ 6.3. SAHBA AJ 6.4. Terphenyl (α-Helix Mimicry) AJ 6.5. Natural Products and their Derivatives AK 6.5.1. Antimycin A3 AK 6.5.2. Chelerythrine AK 6.5.3. Polyphenolic Compounds AK 6.6. Synthetic Molecules AM 6.6.1. HA14-1 AM 6.6.2. BH3Is AM 6.6.3. YC137 AM 6.6.4. ABT-737 AN 6.7. Bax Activators AN 6.8. BAX Inhibitors AN 7. Case Study 6: Small Molecule Modulators of 14-33 PPI AP 7.1. Stabilizers of 14-3-3 PPI AP 7.1.1. Fusicoccin A AP 7.1.2. Pyrrolidone and Epibestatin AR 7.2. Inhibitors of 14-3-3 PPI AS 7.2.1. Fobisin 101 AS 7.2.2. Molecular Tweezers AT 8. Concluding Remarks and Future Outlook AT Author Information AU Corresponding Author AU