Terapia dell'epatite C: identificazione di nuove molecole attive su diversi bersagli

Il virus dell'epatite C (HCV) è l'agente eziologico di una grave forma di epatite trasmessa per via parenterale. Le proteine codificate dal genoma virale rappresentano un appetibile target per lo sviluppo di farmaci antivirali. Le classi di molecole che abbiamo saggiato per la loro attività  inibente sui diversi enzimi sono numerose. Esse possono essere raggruppate in due famiglie, gli analoghi di struttura nucleosidi e i composti non-nucleosidici

Sintesi ed attività biologica di diossolo[4,5-f]indoli-3-beta-diketoacidi e studi di docking nel sito attivo dell'enzima HIV-1 integrasi

In precedenti comunicazioni stata riportata la sintesi di indoli 2-(3-)-β-diketoacidi 1a-f e 2a,c,e. In questo studio è riportata la sintesi, l'attività  biologica e gli studi di modellistica molecolare condotti sui derivati 2b,d a completamento delle precedenti ricerche

In Vitro Antiviral Activity of Hyperbranched Poly-L-Lysine Modified by L-Arginine against Different SARS-CoV-2 Variants

The emergence of SARS-CoV-2 variants requires close monitoring to prevent the reoccurrence of a new pandemic in the near future. The Omicron variant, in particular, is one of the fastest-spreading viruses, showing a high ability to infect people and evade neutralization by antibodies elicited upon infection or vaccination. Therefore, the search for broad-spectrum antivirals that can inhibit the infectious capacity of SARS-CoV-2 is still the focus of intense research. In the present work, hyperbranched poly-L-lysine nanopolymers, which have shown an excellent ability to block the original strain of SARS-CoV-2 infection, were modified with L-arginine. A thermal reaction at 240 degrees C catalyzed by boric acid yielded Lys-Arg hyperbranched nanopolymers. The ability of these nanopolymers to inhibit viral replication were assessed for the original, Delta, and Omicron strains of SARS-CoV-2 together with their cytotoxicity. A reliable indication of the safety profile and effectiveness of the various polymeric compositions in inhibiting or suppressing viral infection was obtained by the evaluation of the therapeutic index in an in vitro prevention model. The hyperbranched L-arginine-modified nanopolymers exhibited a twelve-fold greater therapeutic index when tested with the original strain. The nanopolymers could also effectively limit the replication of the Omicron strain in a cell culture

Structure-Based Identification of HIV-1 Nucleocapsid Protein Inhibitors Active against Wild-Type and Drug-Resistant HIV-1 Strains

HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of the HIV-1 life cycle are efficient in blocking viral replication but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need for novel drug candidates as well as novel putative drug targets. In this respect, pharmacological inhibition of the highly conserved and multifunctional nucleocapsid protein (NC) of HIV-1 is considered a promising alternative to current drugs, particularly to overcome DR. Here, using a multidisciplinary approach combining in silico screening, fluorescence-based molecular assays, and cellular antiviral assays, we identified nordihydroguaiaretic acid (6), as a novel natural product inhibitor of NC. By using NMR, mass spectrometry, fluorescence spectroscopy, and molecular modeling, 6 was found to act through a dual mechanism of action never highlighted before for NC inhibitors (NCIs). First, the molecule recognizes and binds NC noncovalently, which results in the inhibition of the nucleic acid chaperone properties of NC. In a second step, chemical oxidation of 6 induces a potent chemical inactivation of the protein. Overall, 6 inhibits NC and the replication of wild-type and drug-resistant HIV-1 strains in the low micromolar range with moderate cytotoxicity that makes it a profitable tool compound as well as a good starting point for the development of pharmacologically relevant NCIs

Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor

Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue <i><b>R</b></i>_{<i><b>P</b></i>}<i><b>-</b></i><b>13s</b> (IDX899) having an EC₅₀ of 11 nM against the Y181C/K103N double mutant