Giuliana Cuzzucoli Crucitti
Sapienza University of Rome
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Featured researches published by Giuliana Cuzzucoli Crucitti.
Antimicrobial Agents and Chemotherapy | 2014
Angela Corona; Francesco Saverio Di Leva; Sylvain Thierry; Luca Pescatori; Giuliana Cuzzucoli Crucitti; Frédéric Subra; Olivier Delelis; Francesca Esposito; Giuseppe Rigogliuso; Roberta Costi; Sandro Cosconati; Ettore Novellino; Roberto Di Santo; Enzo Tramontano
ABSTRACT HIV-1 reverse transcriptase (RT)-associated RNase H activity is an essential function in viral genome retrotranscription. RNase H is a promising drug target for which no inhibitor is available for therapy. Diketo acid (DKA) derivatives are active site Mg2+-binding inhibitors of both HIV-1 RNase H and integrase (IN) activities. To investigate the DKA binding site of RNase H and the mechanism of action, six couples of ester and acid DKAs, derived from 6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester (RDS1643), were synthesized and tested on both RNase H and IN functions. Most of the ester derivatives showed selectivity for HIV-1 RNase H versus IN, while acids inhibited both functions. Molecular modeling and site-directed mutagenesis studies on the RNase H domain demonstrated different binding poses for ester and acid DKAs and proved that DKAs interact with residues (R448, N474, Q475, Y501, and R557) involved not in the catalytic motif but in highly conserved portions of the RNase H primer grip motif. The ester derivative RDS1759 selectively inhibited RNase H activity and viral replication in the low micromolar range, making contacts with residues Q475, N474, and Y501. Quantitative PCR studies and fluorescence-activated cell sorting (FACS) analyses showed that RDS1759 selectively inhibited reverse transcription in cell-based assays. Overall, we provide the first demonstration that RNase H inhibition by DKAs is due not only to their chelating properties but also to specific interactions with highly conserved amino acid residues in the RNase H domain, leading to effective targeting of HIV retrotranscription in cells and hence offering important insights for the rational design of RNase H inhibitors.
Journal of Medicinal Chemistry | 2015
Giuliana Cuzzucoli Crucitti; Mathieu Métifiot; Luca Pescatori; Antonella Messore; Valentina Noemi Madia; Giovanni Pupo; Francesco Saccoliti; Luigi Scipione; Silvano Tortorella; Francesca Esposito; Angela Corona; Marta Cadeddu; Christophe Marchand; Yves Pommier; Enzo Tramontano; Roberta Costi; Roberto Di Santo
The development of HIV-1 dual inhibitors is a highly innovative approach aimed at reducing drug toxic side effects as well as therapeutic costs. HIV-1 integrase (IN) and reverse transcriptase-associated ribonuclease H (RNase H) are both selective targets for HIV-1 chemotherapy, and the identification of dual IN/RNase H inhibitors is an attractive strategy for new drug development. We newly synthesized pyrrolyl derivatives that exhibited good potency against IN and a moderate inhibition of the RNase H function of RT, confirming the possibility of developing dual HIV-1 IN/RNase H inhibitors and obtaining new information for the further development of more effective dual HIV-1 inhibitors.
Journal of Medicinal Chemistry | 2008
Roberto Di Santo; Roberta Costi; Alessandra Roux; Gaetano Miele; Giuliana Cuzzucoli Crucitti; Alberto Iacovo; Federica Rosi; Antonio Lavecchia; Luciana Marinelli; Carmen Di Giovanni; Ettore Novellino; Lucia Palmisano; Mauro Andreotti; Roberta Amici; Clementina Maria Galluzzo; Lucia Nencioni; Anna Teresa Palamara; Yves Pommier; Christophe Marchand
Novel quinolinonyl diketo acids were designed to obtain integrase (IN) inhibitors selectively active against the strand transfer (ST) step of the HIV integration process. Those new compounds are characterized by a single aryl diketo acid (DKA) chain in comparison to 4, a bifunctional diketo acid reported by our group as an anti-IN agent highly potent against both the 3′-processing and ST steps. Compound 6d was the most potent derivative in IN enzyme assays, while 6i showed the highest potency against HIV-1 in acutely infected cells. The selective inhibition of ST suggested the newly designed monofunctional DKAs bind the IN−DNA acceptor site without affecting the DNA donor site.
Bioorganic & Medicinal Chemistry | 2012
Rossella Fioravanti; Ignacio Celestino; Roberta Costi; Giuliana Cuzzucoli Crucitti; Luca Pescatori; Leonardo Mattiello; Ettore Novellino; Paola Checconi; Anna Teresa Palamara; Lucia Nencioni; Roberto Di Santo
A set of polyphenol compounds was synthesized and assayed for their ability in inhibiting influenza A virus replication. A sub-set of them showed low toxicity. The best compounds within this sub-set were 4 and 6g, which inhibited the viral replication in a dose-dependent manner. The antiviral activity of these molecules was demonstrated to be caused by their interference with intracellular pathways exploited for viral replication: (1) MAP kinases controlling nuclear-cytoplasmic traffic of viral ribonucleoprotein complex; (2) redox-sensitive pathways, involved in maturation of viral hemagglutinin protein.
Journal of Medicinal Chemistry | 2012
Guido Furlotti; Maria Alessandra Alisi; Claudia Apicella; Alessandra Capezzone de Joannon; Nicola Cazzolla; Roberta Costi; Giuliana Cuzzucoli Crucitti; Beatrice Garrone; Alberto Iacovo; Gabriele Magarò; Giorgina Mangano; Gaetano Miele; Rosella Ombrato; Luca Pescatori; Lorenzo Polenzani; Federica Rosi; Marco Vitiello; Roberto Di Santo
Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl]-1H-indazole-3-carboxamide and 4-[(4-piperidinyl)methoxy]-2H-pyrrolo[3,4-c]quinoline derivatives as new 5-HT(4)R ligands endowed with high selectivity over the serotonin 2A receptor and human ether-a-go-go-related gene potassium ion channel. Within these series, two molecules (11 ab and 12 g) were identified as potent and selective 5-HT(4)R antagonists with good in vitro pharmacokinetic properties. These compounds were evaluated for their antinociceptive action in two analgesia animal models. 12 g showed a significant antinociceptive effect in both models and is proposed as an interesting lead compound as a 5-HT(4)R antagonist with analgesic action.
Journal of Medicinal Chemistry | 2012
Roberto Di Santo; Roberta Costi; Giuliana Cuzzucoli Crucitti; Luca Pescatori; Federica Rosi; Luigi Scipione; Diana Celona; Mario Vertechy; Orlando Ghirardi; Paola Piovesan; Mauro Marzi; Silvio Caccia; Giovanna Guiso; Fabrizio Giorgi; Patrizia Minetti
Dyes like CR are able to inhibit the aggregation of Aβ fibrils. Thus, a screening of a series of dyes including ABBB (1) was performed. Its main component 2 tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners 4-9 have been designed and synthesized as inhibitors of Aβ aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC(50) of 1-57.4 μM. The most potent compound of this series, 4k, showed micromolar activity in this test. Another potent derivative 4q (IC(50) = 5.6 μM) rapidly crossed the blood-brain barrier, achieving whole brain concentrations higher than in plasma. So 4q could be developed to find novel potent antiaggregating βA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates.
Journal of Medicinal Chemistry | 2013
Roberta Costi; Giuliana Cuzzucoli Crucitti; Luca Pescatori; Antonella Messore; Luigi Scipione; Silvano Tortorella; Alessandra Amoroso; Emmanuele Crespan; Pietro Campiglia; Bruno Maresca; Amalia Porta; Ilaria Granata; Ettore Novellino; Jeŕo ̂me Gouge; Marc Delarue; Giovanni Maga; Roberto Di Santo
Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol μ during the mutagenic repair of double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that specifically target TdT and behave as nucleotide-competitive inhibitors. These compounds show a selective toxicity toward MOLT-4 compared to HeLa cells that correlate well with in vitro selectivity for TdT. The binding site of two of these inhibitors was determined by cocrystallization with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide triphosphate (dNTP). In addition, because of the observed dual localization of the phenyl substituent, these studies open the possibility of rationally designing more potent compounds.
Journal of Enzyme Inhibition and Medicinal Chemistry | 2016
Kusal K. Das; Nima Razzaghi-Asl; Swati N. Tikare; Roberto Di Santo; Roberta Costi; Antonella Messore; Luca Pescatori; Giuliana Cuzzucoli Crucitti; Jameel G. Jargar; Salim A. Dhundasi; Luciano Saso
Abstract The currently available therapies for type 2 diabetes have been unable to achieve normoglycemic status in the majority of patients. The reason may be attributed to the limitations of the drug itself or its side effects. In an effort to develop potent and safe oral antidiabetic agents, we evaluated the in vitro and in vivo hypoglycemic effects of 10 synthetic polyphenolic curcumin analogues on alloxan-induced male diabetic albino rats. In vitro studies showed 7-bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione (4) to be the most potential hypoglycemic agent followed by 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one (10). Structure activity relationship (SAR) of the tested compounds was elucidated and the results were interpreted in terms of in vitro hypoglycemic activities. Furthermore, oral glucose tolerance test (OGTT) with compounds 4, 10 and reference hypoglycemic drug glipizide showed that compound 4 and glipizide had relatively similar effects on the reduction of blood glucose levels within 2 h. Thus, compound 4 might be regarded as a potential hypoglycemic agent being able to reduce glucose concentration both in vitro and in vivo.
Current HIV Research | 2012
Giuliana Cuzzucoli Crucitti; Maurizio Botta; Roberto Di Santo
Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections including HIV-1. Despite more than two decades of HIV-1 research, there is still no efficacious HIV-1 vaccine, and the scientific community appears sceptical about the short or long-term feasibility of developing a vaccine that has the ability to induce sterilizing immunity against HIV-1. In this setting, microbicide research has been developed. Among the promising candidate microbicides, the integrase inhibitors are the most recently developed compounds. In fact, since the beginning reverse transcriptase, fusion and entry inhibitors were identified as possible HIV-specific candidate microbicides along with the non-specific topical microbicides. In the case of integrase inhibitors, only a few have demonstrated to block HIV-1 infection in models that mimic sexual transmission of the virus. These compounds have been tested in in vitro and ex vivo assays to determine their efficacy in pre- and/or post-exposure prophylactic settings. In particular, the naphthyridinecarboxyamide L-870,812 has been shown to block viral infection in pre- and post-exposure studies obtaining comparable results to the reverse transcriptase inhibitor PMPA. The purpose of this article is to provide an overview of integrase inhibitors as potential topical microbicides and their comparative evaluation with HIV-specific and non-specific microbicides.
Synthetic Communications | 2013
Federica Rosi; Giuliana Cuzzucoli Crucitti; Alberto Iacovo; Gaetano Miele; Luca Pescatori; Roberto Di Santo; Roberta Costi
Abstract A practical and versatile method for the synthesis of 2H-pyrrolo[3,4-b]quinolin-9(4H)-one skeleton via tosylmethyl isocyanide (TosMIC) reaction has been developed. Many attempts have been made to reverse the null reactivity of 4-hydroxyquinoline and its N-alkyl derivatives toward TosMIC reactant. For this reason various molecular modifications have been improved for the purpose of obtaining a reactive substrate. tert-Butyl-4-oxoquinoline-1(4H)-carboxylate resulted in the best substrate to provide the desired tricyclic system via facile TosMIC reaction. GRAPHICAL ABSTRACT