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1. Suramin binds and inhibits infection of SARS-CoV-2 through both spike protein-heparan sulfate and ACE2 receptor interactions

   https://doi.org/10.1038/s42003-023-04789-z  

   Kwon, Paul S.; Xu, Shirley; Oh, Hanseul; Kwon, Seok-Joon; Rodrigues, Andre L.; Feroz, Maisha; Fraser, Keith; He, Peng; Zhang, Fuming; Hong, Jung Joo; et al (December 2023, Communications Biology)

   Abstract SARS-CoV-2 receptor binding domains (RBDs) interact with both the ACE2 receptor and heparan sulfate on the surface of host cells to enhance SARS-CoV-2 infection. We show that suramin, a polysulfated synthetic drug, binds to the ACE2 receptor and heparan sulfate binding sites on the RBDs of wild-type, Delta, and Omicron variants. Specifically, heparan sulfate and suramin had enhanced preferential binding for Omicron RBD, and suramin is most potent against the live SARS-CoV-2 Omicron variant (B.1.1.529) when compared to wild type and Delta (B.1.617.2) variants in vitro. These results suggest that inhibition of live virus infection occurs through dual SARS-CoV-2 targets of S-protein binding and previously reported RNA-dependent RNA polymerase inhibition and offers the possibility for this and other polysulfated molecules to be used as potential therapeutic and prophylactic options against COVID-19. 

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2. Insights into the action of the pharmaceutical metformin: Targeted inhibition of the gut microbial enzyme agmatinase

   https://doi.org/10.1016/j.isci.2024.108900  

   Tassoulas, Lambros J; Wackett, Lawrence P (February 2024, iScience)

   Muzzio, Michelle (Ed.)

   Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully under- stood. Recent studies suggest metformin’s interactions with gut microbiota are responsible for exerting therapeutic effects. In this study, we report that metformin targets the gut microbial enzyme agmatinase, as a competitive inhibitor, which may impair gut agmatine catabolism. The metformin inhibition constant (Ki) of E. coli agmatinase is 1 mM and relevant in the gut where the drug concentration is 1–10 mM. Met- formin analogs phenformin, buformin, and galegine are even more potent inhibitors of E. coli agmatinase (Ki = 0.6, 0.1, and 0.007 mM, respectively) suggesting a shared mechanism. Agmatine is a known effector of human host metabolism and has been reported to augment metformin’s therapeutic effects for type 2 diabetes. This gut-derived inhibition mechanism gives new insights on metformin’s action in the gut and may lead to significant discoveries in improving metformin therapy. 

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3. Design of Potent Panobinostat Histone Deacetylase Inhibitor Derivatives: Molecular Considerations for Enhanced Isozyme Selectivity between HDAC2 and HDAC8

   https://doi.org/10.1002/minf.201800080  

   Stoddard, Shana V.; May, Xavier A.; Rivas, Fatima; Dodson, Kyra; Vijayan, Sajith; Adhika, Swetha; Parker, Kordarius; Watkins, Davita L. (October 2018, Molecular Informatics)

   Abstract Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti‐cancer, neurodegenerative, immunological, and anti‐parasitic agents. Design of potent HDAC2 and HDAC8 inhibitors will be useful for the therapeutic advances in many disorders. This work was undertaken to develop potent HDAC2 and HDAC8 inhibitors. A docking study was performed comparing panobinostat derivatives in both HDAC2 and HDAC8. Six of our derivatives showed stronger binding to HDAC2 than panobinostat, and two of our derivatives showed stronger binding to HDAC8 than panobinostat. We evaluated the molecular features, which improved potency of our inhibitors over panobinostat and also identified another molecular consideration, which could be used to enhance histone deacetylase inhibitor (HDACi) selectivity towards either the HDAC2 or HDAC8 isozymes. The results of this work can be used to assist future design of more potent and selective HDACi for HDAC2 and HDAC8. 

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4. Derivatives of the Fungal Natural Product Illudalic Acid Inhibit the Activity of Protein Histidine Phosphatase PHPT1

   https://doi.org/10.1002/cmdc.202300187  

   Wang, Hanfei; Gaston, Jr., Robert; Ahmed, Kh_Tanvir; Dudley, Gregory_B; Barrios, Amy_M (June 2023, ChemMedChem)

   Abstract PHPT1 is a protein histidine phosphatase that has been implicated in several disease pathways, but the chemical tools necessary to study the biological roles of this enzyme and investigate its utility as a therapeutic target have yet to be developed. To this end, the discovery of PHPT1 inhibitors is an area of significant interest. Here, we report an investigation of illudalic acid and illudalic acid analog‐based inhibition of PHPT1 activity. Four of the seven analogs investigated had IC₅₀values below 5 μM, with the most potent compound (IA1‐8H2) exhibiting an IC₅₀value of 3.4±0.7 μM. Interestingly, these compounds appear to be non‐covalent, non‐competitive inhibitors of PHPT1 activity, in contrast to other recently reported PHPT1 inhibitors. Mutating the three cysteine residues to alanine has no effect on inhibition, indicating that cysteine is not critical for interactions between inhibitor and enzyme. 

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5. Development of 4-[4-(Anilinomethyl)-3-phenyl-pyrazol-1-yl] Benzoic Acid Derivatives as Potent Anti-Staphylococci and Anti-Enterococci Agents

   https://doi.org/10.3390/antibiotics11070939  

   Raj KC, Hansa; Gilmore, David F.; Alam, Mohammad A. (July 2022, Antibiotics)

   From a library of compounds, 11 hit antibacterial agents have been identified as potent anti-Gram-positive bacterial agents. These pyrazole derivatives are active against two groups of pathogens, staphylococci and enterococci, with minimum inhibitory concentration (MIC) values as low as 0.78 μg/mL. These potent compounds showed bactericidal action, and some were effective at inhibiting and eradicating Staphylococcus aureus and Enterococcus faecalis biofilms. Real-time biofilm inhibition by the potent compounds was studied, by using Bioscreen C. These lead compounds were also very potent against S. aureus persisters as compared to controls, gentamycin and vancomycin. In multiple passage studies, bacteria developed little resistance to these compounds (no more than 2 × MIC). The plausible mode of action of the lead compounds is the permeabilization of the cell membrane determined by flow cytometry and protein leakage assays. With the detailed antimicrobial studies, both in planktonic and biofilm contexts, some of these potent compounds have the potential for further antimicrobial drug development. 

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