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Sellitto G.,University of Salerno | Faruolo A.,University of Salerno | De Caprariis P.,University of Salerno | Altamura S.,Istituto di Ricerche di Biologia Molecolare | And 2 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

A series of ethyl 1H-indole-3-carboxylates 9a1- 6 and 9b1-2 were prepared and evaluated in Huh-7.5 cells. Most of the compounds exhibited anti-hepatitis C virus (HCV) activities at low concentration. The selectivity indices of inhibition on entry and replication of compounds 9a2 (>10; >16.7) and 9b1 (>6.25; >16.7) were higher than those of the other evaluated compounds, including the lead compound Arbidol (ARB, 6; 15). Moreover, the selective index of inhibition on entry of compound 9a3 (>6.25) was higher than that of ARB (6). Of these three initial hits, compound 9a2 was the most potent. © 2010 Elsevier Ltd. All rights reserved. Source


Powdrill M.H.,McGill University | Deval J.,McGill University | Deval J.,Roche Holding AG | Narjes F.,Istituto di Ricerche di Biologia Molecolare | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

We studied the biochemical mechanisms associated with inhibition and resistance to a 4,5-dihydroxypyrimidine carboxylate that inhibits the hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B. On the basis of the structure of the pharmacophore, it has been suggested that these compounds may act as pyrophosphate (PPi) mimics. We monitored nucleotide incorporation events during the elongation phase and showed that the polymerase activity of wild-type NS5B was inhibited by the dihydroxypyrimidine at a 50% inhibitory concentration (IC50) of 0.73 μM. Enzymes with the G152E or P156L mutation, either of which confers resistance to this compound, showed four- to fivefold increases in IC50s. The inhibitor was competitive with respect to nucleotide incorporation. It was likewise effective at preventing the PPi-mediated excision of an incorporated chain terminator in a competitive fashion. In the absence of the dihydroxypyrimidine, the reaction was not significantly affected by the G152E or P156L mutation. These data suggest that the resistance associated with these two mutations is unlikely due to an altered interaction with the pyrophosphate-mimicking domain of the compound but, rather, is due to altered interactions with its specificity domain at a region distant from the active site. Together, our findings provide strong experimental evidence that supports the notion that the members of this class of compounds can act as PPi mimics that have the potential to mechanistically complement established nucleoside and nonnucleoside analogue inhibitors. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source


Michelini Z.,Istituto Superiore di Sanita | Galluzzo C.M.,Istituto Superiore di Sanita | Negri D.R.M.,Parasitic and Immune mediated Diseases | Leone P.,Istituto Superiore di Sanita | And 10 more authors.
Journal of Virological Methods | Year: 2010

Macrophages represent an important site for productive infection of HIV-1 and the evaluation of integrase (IN) inhibitors on this cell subset is of fundamental importance. In this report, preclinical evaluation of IN inhibitors on primary human macrophages was attempted successfully using a 96-well microtiter phenotypic assay developed recently for the evaluation of IN inhibitors in a cell-based system by taking advantage of HIV-derived lentiviral vectors expressing luciferase. IN inhibitors were also tested using a lentiviral vector containing an IN with introduced T66I/S153Y mutations, known to affect the activity of azido-group-containing diketo acid (DKA) IN inhibitors. Utilizing different classes of HIV integrase inhibitors against the wild-type IN and the mutant mentioned above, some of the IN inhibitors used were also active on this particular mutant, suggesting that should HIV-1 develop additional or different mutations to become resistant to such anti-IN drugs, new drugs can be developed with a better resistance profile. This assay provides a standardized method for the preclinical evaluation of the efficacy of IN inhibitors on wild-type and mutated IN that can be adapted easily for the evaluation of anti-IN activity on IN sequences derived from patients. © 2010 Elsevier B.V. Source


Jones P.,Istituto di Ricerche di Biologia Molecolare | Jones P.,Anderson University, South Carolina | Wilcoxen K.,TESARO | Rowley M.,Istituto di Ricerche di Biologia Molecolare | And 3 more authors.
Journal of Medicinal Chemistry | Year: 2015

Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. It is currently being tested in phase 3 clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer. © 2015 American Chemical Society. Source


Peruzzi D.,Istituto di Ricerche di Biologia Molecolare | Mesiti G.,Istituto di Ricerche di Biologia Molecolare | Ciliberto G.,Istituto di Ricerche di Biologia Molecolare | La Monica N.,Istituto di Ricerche di Biologia Molecolare | Aurisicchio L.,Istituto di Ricerche di Biologia Molecolare
Vaccine | Year: 2010

Pet dogs represent a valuable pre-clinical model to assess the efficacy of oncology drugs. Additionally, canine cancers occur with an incidence similar to that of humans and share many features with human malignancies including histological appearance, tumor genetics, biological behavior and response to conventional therapies. The telomerase reverse transcriptase (TERT) is reactivated in most of human and dog tumors. Similarly, HER-2/neu oncoprotein is overexpressed in a proportion of canine breast cancers. Therefore, TERT and HER-2/neu can constitute valid tumor associated antigens (TAA), suitable targets for translational cancer immunotherapy in dogs. In this study, we have evaluated the ability of DNA electroporation (DNA-EP) and Adenovirus serotype 6 (Ad6) to induce immune responses against dog TERT (dTERT) and HER-2/neu in healthy dogs. Vaccination was effective in all treated animals and the adaptive immune response remained detectable and long-lasting in the absence of autoimmunity or other side-effects. Our results show that DNA-EP/Ad6-based cancer vaccine induces adaptive immune responses against TAA in canine subjects and support further evaluation of this approach in cancer dog patients. © 2009 Elsevier Ltd. All rights reserved. Source

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