Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor

AbstractRNA dependent RNA polymerases (RdRp) are essential enzymes for flavivirus replication. Starting from an in silico docking analysis we identified a pyridobenzothiazole compound, HeE1-2Tyr, able to inhibit West Nile and Dengue RdRps activity in vitro, which proved effective against different flaviviruses in cell culture. Crystallographic data show that HeE1-2Tyr binds between the fingers domain and the priming loop of Dengue virus RdRp (Site 1). Conversely, enzyme kinetics, binding studies and mutational analyses suggest that, during the catalytic cycle and assembly of the RdRp-RNA complex, HeE1-2Tyr might be hosted in a distinct binding site (Site 2). RdRp mutational studies, driven by in silico docking analysis, allowed us to locate the inhibition Site 2 in the thumb domain. Taken together, our results provide innovative concepts for optimization of a new class of anti-flavivirus compounds

1,2,4-Triazolo[1,5-a]pyrimidines as a Novel Class of Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity

Despite great efforts have been made in the prevention and therapy of human immunodeficiency virus (HIV-1) infection, however the difficulty to eradicate latent viral reservoirs together with the emergence of multi-drug-resistant strains require the search for innovative agents, possibly exploiting novel mechanisms of action. In this context, the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H), which is one of the few HIV-1 encoded enzymatic function still not targeted by any current drug, can be considered as an appealing target. In this work, we repurposed in-house anti-influenza derivatives based on the 1,2,4-triazolo[1,5-a]-pyrimidine (TZP) scaffold for their ability to inhibit HIV-1 RNase H function. Based on the results, a successive multi-step structural exploration around the TZP core was performed leading to identify catechol derivatives that inhibited RNase H in the low micromolar range without showing RT-associated polymerase inhibitory activity. The antiviral evaluation of the compounds in the MT4 cells showed any activity against HIV-1 (IIIB strain). Molecular modelling and mutagenesis analysis suggested key interactions with an unexplored allosteric site providing insights for the future optimization of this class of RNase H inhibitors

Structural Modifications of the Quinolin-4-yloxy Core to Obtain New Staphylococcus aureus NorA Inhibitors

: Tackling antimicrobial resistance (AMR) represents a social responsibility aimed at renewing the antimicrobial armamentarium and identifying novel therapeutical approaches. Among the possible strategies, efflux pumps inhibition offers the advantage to contrast the resistance against all drugs which can be extruded. Efflux pump inhibitors (EPIs) are molecules devoid of any antimicrobial activity, but synergizing with pumps-substrate antibiotics. Herein, we performed an in silico scaffold hopping approach starting from quinolin-4-yloxy-based Staphylococcus aureus NorA EPIs by using previously built pharmacophore models for NorA inhibition activity. Four scaffolds were identified, synthesized, and modified with appropriate substituents to obtain new compounds, that were evaluated for their ability to inhibit NorA and synergize with the fluoroquinolone ciprofloxacin against resistant S. aureus strains. The two quinoline-4-carboxamide derivatives 3a and 3b showed the best results being synergic (4-fold MIC reduction) with ciprofloxacin at concentrations as low as 3.13 and 1.56 µg/mL, respectively, which were nontoxic for human THP-1 and A549 cells. The NorA inhibition was confirmed by SA-1199B ethidium bromide efflux and checkerboard assays against the isogenic pair SA-K2378 (norA++)/SA-K1902 (norA-). These in vitro results indicate the two compounds as valuable structures for designing novel S. aureus NorA inhibitors to be used in association with fluoroquinolones

Il Banco di San Giorgio : l'antico debito pubblico genovese e la Casa di S. Giorgio, la Marina di Genova, S. Giorgio e i possedimenti coloniali di terraferma, il palazzo della società e le sue dipendenze

Il Banco di San Giorgio : l'antico debito pubblico genovese e la Casa di S. Giorgio, la Marina di Genova, S. Giorgio e i possedimenti coloniali di terraferma, il palazzo della società e le sue dipendenze / Emilio Marengo, Camillo Manfroni, Giuseppe Pessagno Genova : A. Donath, 1911 556 p. : ill., [1] carta di tav. ; 35 cm Sul frontespizio: A cura e per decreto del Consorzio autonomo del Porto. Titolo dell'occhietto: Il banco di San Giorgio

A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates

Hepatitis C virus (HCV) infection is a global health burden with an estimated 130-170 million chronically infected individuals and is the cause of serious liver diseases such as cirrhosis and hepatocellular carcinoma. HCV NS4B protein represents a validated target for the identification of new drugs to be added to the combination regimen recently approved. During the last years, NS4B has thus been the object of impressive medicinal chemistry efforts, which led to the identification of promising preclinical candidates. In this context, the present review aims to discuss research published on NS4B functional inhibitors focusing the attention on hit identification, hit-to-lead optimization, ADME profile evaluation, and the structure-activity relationship data raised for each compound family taken into account. The information delivered in this review will be a useful and valuable tool for those medicinal chemists dealing with research programs focused on NS4B and aimed at the identification of innovative anti-HCV compounds

Small Molecule Drugs Targeting Viral Polymerases

Small molecules that specifically target viral polymerases—crucial enzymes governing viral genome transcription and replication—play a pivotal role in combating viral infections. Presently, approved polymerase inhibitors cover nine human viruses, spanning both DNA and RNA viruses. This review provides a comprehensive analysis of these licensed drugs, encompassing nucleoside/nucleotide inhibitors (NIs), non-nucleoside inhibitors (NNIs), and mutagenic agents. For each compound, we describe the specific targeted virus and related polymerase enzyme, the mechanism of action, and the relevant bioactivity data. This wealth of information serves as a valuable resource for researchers actively engaged in antiviral drug discovery efforts, offering a complete overview of established strategies as well as insights for shaping the development of next-generation antiviral therapeutics

Structure-based insights into p38α MAPK: from crystal structures analysis to hit optimization

p38α mitogen-activated protein kinase (MAPK) is a serine/threonine kinase involved in the regulation of pro-inflammatory signaling networks and in the biosynthesis of cytokines, representing a well-recognized therapeutic target for the treatment of autoimmune and inflammatory diseases.1 Over the past two decades, tremendous efforts have been focused on the discovery and development of small-molecule acting as p38α MAPK inhibitors, although no drugs targeting this protein are currently available.2 Thus, the discovery and development of novel small molecule p38α inhibitors represent an exciting area of research. In this context, we have recently identified the pyrazolobenzothiazine core as a new p38αMAPK inhibitor chemoptype.3 Some derivatives showed interesting activity in both p38α MAPK and TNF-α release assays, coupled with a promising kinase selectivity profile. The binding mode prediction of the best hits (Figure 1) has provided clues for further chemical optimization. Towards this aim, first an in depth analysis of the available crystal structures of p38α MAPK in complex with ATP competitive type I inhibitors (TI-Is)4 has been carried out, getting insights into ATP binding site conformations and key inhibitor features. Building on this, we have analysed the impact of protein target conformations on automated molecular docking and docking-based virtual screening. The information gathered from such modelling studies is currently used to aid both our hit-to-lead optimization strategy and the rational identification of new p38a MAPK inhibitor chemotypes through virtual screening campaigns