Publications by authors named "Francesco Orofino"

5 Publications

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Viral Envelope Membrane: A Special Entry Pathway and a Promising Drug Target.

Curr Med Chem 2021 Feb 18. Epub 2021 Feb 18.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, . Italy.

Enveloped viruses belong to a large class of pathogens responsible for multiple serious diseases. Their spread into new territories has been the cause of major epidemics throughout human history, including the Spanish flu in 1918 and the latest COVID-19 pandemic. Thanks to their outer membrane, consisting essentially of host lipids, enveloped viruses are more resistant to enzymes, and are also less susceptible to host immune defenses than their naked counterparts. Therefore, the development of effective approaches to combat enveloped virus infections represents a major challenge for antiviral therapy in the current century. This review focuses on the characteristics of enveloped viruses, their importance in the entry phase, drugs targeting envelope membrane-mediated entry, and those specifically designed to target the envelope. The broad-spectrum antiviral activity of these compounds can be attributed to their ability to affect the envelope, an essential structural feature common to several viruses. This makes this class of compounds agents of great interest when no specific drugs or vaccines are available to block viral infections.
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http://dx.doi.org/10.2174/0929867328666210218182203DOI Listing
February 2021

Computational drug repurposing for the identification of SARS-CoV-2 main protease inhibitors.

J Biomol Struct Dyn 2021 10 24;39(16):6242-6248. Epub 2020 Jul 24.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.

Accepted 7 July 2020ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the known COVID-19 disease. Since currently no definitive therapies or vaccines for the SARS-CoV-2 virus are available, there is an urgent need to identify effective drugs against SARS-CoV-2 infection. One of the best-known targets available is the main protease of this virus, crucial for the processing of polyproteins codified by viral RNA. In this work, we used a computational virtual screening procedure for the repurposing of commercial drugs available in the DrugBank database as inhibitors of the SARS-CoV-2 main protease. Molecular docking calculations and molecular dynamics (MD) simulations have been applied. The computational model was validated through a self-docking procedure. The screening procedure highlighted five interesting drugs that showed a comparable or higher docking score compared to the crystallographic compound and maintained the protein binding during the MD runs. Amongst these drugs, Ritonavir has been used in clinical trials with patients affected by COVID-19 and Nelfinavir showed anti-SARS-CoV-2 activity. The five identified drugs could be evaluated experimentally as inhibitors of the SARS-CoV-2 main protease in view of a possible COVID-19 treatment. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1796805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441760PMC
October 2021

AuNP Pyrazolo[3,4-]pyrimidine Nanosystem in Combination with Radiotherapy against Glioblastoma.

ACS Med Chem Lett 2020 May 5;11(5):664-670. Epub 2020 Mar 5.

Dipartimento Biotecnologie, Chimica e Farmacia, UniversitĂ  degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.

Gold-nanoparticle (AuNP)-conjugated drugs represent a promising and innovative antitumor therapeutic approach. In our study, we describe the design, the synthesis, the preparation, and the characterization of AuNPs conjugated with the pyrazolo[3,4-]pyrimidine derivative SI306, a c-Src inhibitor. AuNPs-SI306 showed a good loading efficacy (65%), optimal stability in polar media and in human plasma, and a suitable morphological profile: a ζ-potential of -43.9 mV, a nanoparticle diameter of 48.6 nm, and a 0.441 PDI value. The antitumoral activity of AuNPs-SI306 was evaluated in the glioblastoma model, by the low-density growth assay, and also in combination with radiotherapy (RT). Results demonstrated that AuNPs had a basal radiosensitization ability and that AuNPs-SI306, when used in combination with RT, were more effective in inhibiting tumor cell growth with respect to AuNPs and free SI306.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236040PMC
May 2020

In vitro characterization, ADME analysis, and histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains.

Int J Antimicrob Agents 2020 Mar 20;55(3):105865. Epub 2019 Dec 20.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy; Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Philadelphia, PA 19122, USA.

Background: Candida species are one of the most common causes of nosocomial bloodstream infections among the opportunistic fungi. Extensive use of antifungal agents, most of which were launched on the market more than 20 years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. We recently described a novel class of antifungal macrocyclic compounds with an amidinourea moiety that is highly active against azole-resistant Candida strains.

Objective: A compound from this family, BM1, was investigated in terms of in vitro activity against various Candida species, including C. auris isolates, interaction with the ABC transporter, CDR6, and in vivo distribution and safety.

Methods: In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) were used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis were utilised to evaluate in vivo toxicology, pharmacokinetics, and distribution.

Results: The current research shows BM1 has a low in vivo toxicity profile, affinity for the renal system in rats, and good absorption, distribution, metabolism, and excretion (ADME). BM1 also has potent activity against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains.

Conclusions: The results confirmed low minimum inhibitory concentrations (MICs) against several Candida species, including preliminary data vs. C. auris. BM1 has good ADME and biochemical characteristics, is suitable and safe for daily administration and is particularly indicated for renal infections. These data indicate BM1 and its derivatives form a novel, promising antifungal class.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.105865DOI Listing
March 2020

Design and synthesis of a novel inhibitor of T. Viride chitinase through an in silico target fishing protocol.

Bioorg Med Chem Lett 2017 08 10;27(15):3332-3336. Epub 2017 Jun 10.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA; Lead Discovery Siena s.r.l, Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga, Italy. Electronic address:

In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.
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http://dx.doi.org/10.1016/j.bmcl.2017.06.016DOI Listing
August 2017
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