HER2-expressing cancers currently benefit from targeted therapies, including monoclonal antibodies and antibody-drug conjugates that specifically bind to the extracellular domain of the receptor. Peptides targeting HER2 represent promising candidates for the development of alternative molecular drugs. In this study, we report a dimeric version of the previously validated A9 peptide as a ligand specifically targeting HER2. The novel A9-PEG-A9 conjugate consists of two A9 peptides whose N-terminal amino groups are linked via a polyethylene glycol chain. It was synthesized using a solvent-free protocol and validated as an improved ligand, demonstrating enhanced water solubility and increased affinity for the model receptor HER2-DIVMP, as determined by the fluorescence spectroscopy titration method.
A green synthetic protocol to add a chemical function to a fully deprotected peptide to obtain a bioactive and/or fluorescent-labeled conjugate is reported. A range of S-conjugation reactions promoted by the commercially available LTA zeolite to introduce different substituents on peptide cysteine residues has been shown to take place in the solid state or in the presence of minimal amounts of organic solvent, with yields that are comparable to those of standard solution methods. The additional advantage of the procedure consists of easing the work up, for which green solvents, such as aqueous systems, can be employed. The protocol is implemented with microwave irradiation to shorten the reaction time as dielectric heating increases the diffusion rates of the mechanically milled reactants.
The current coronavirus disease-2019 (COVID-19) pandemic is due to the novel coronavirus SARS-CoV-2. The scientific community has mounted a strong response by accelerating research and innovation, and has quickly set the foundation for understanding the molecular determinants of the disease for the development of targeted therapeutic interventions. The replication of the viral genome within the infected cells is a key stage of the SARS-CoV-2 life cycle. It is a complex process involving the action of several viral and host proteins in order to perform RNA polymerization, proofreading and final capping. This review provides an update of the structural and functional data on the key actors of the replicatory machinery of SARS-CoV-2, to fill the gaps in the currently available structural data, which is mainly obtained through homology modeling. Moreover, learning from similar viruses, we collect data from the literature to reconstruct the pattern of interactions among the protein actors of the SARS-CoV-2 RNA polymerase machinery. Here, an important role is played by co-factors such as Nsp8 and Nsp10, not only as allosteric activators but also as molecular connectors that hold the entire machinery together to enhance the efficiency of RNA replication.
Here we report on the most recent updates on experimental drugs successfully employed
in the treatment of the disease caused by SARS-CoV-2 coronavirus, also referred to as
COVID-19 (COronaVIrus Disease 19). In particular, several cases of recovered patients have
been reported after being treated with lopinavir/ritonavir (which is widely used to treat human
immunodeficiency virus (HIV) infection) in combination with the anti-flu drug oseltamivir. In
addition, remdesivir, which has been previously administered to Ebola virus patients, has also
proven effective in the U.S. against coronavirus, while antimalarial chloroquine and hydroxychloroquine,
favipiravir and co-administered darunavir and umifenovir (in patient therapies)
were also recently recorded as having anti-SARS-CoV-2 effects. Since the recoveries/deaths
ratio in the last weeks significantly increased, especially in China, it is clear that the experimental
antiviral therapy, together with the availability of intensive care unit beds in hospitals
and rigorous government control measures, all play an important role in dealing with this virus.
This also stresses the urgent need for the scientific community to devote its efforts to the
development of other more specific antiviral strategies.
The first outbreak of COVID-19 in Italy occurred during the second half of February 2020 in some areas in the North of the country. Due to the high contagiousness of the infection, further spread by asymptomatic people,
Italy has become in a few weeks the country with the greatest number of infected people in the world. The large number of severe cases among infected people in Italy led to the hospitalization of thousands of patients, with a heavy burden on the National Health Service.
Methods
We analyzed data provided daily by Italian Authorities for the period from 24 February 2020 to 30 March 2020. Considering such information, we developed a forecast model in real-time, based on the cumulative log-logistic distribution.
Results
A total of 101,739 infected individuals were confirmed until 30 March 2020, of which 14,620 recovered or discharged, and 11,591 deaths. Until the same date patients quarantined at home were 43,752, whereas hospitalized patients were 31,776, of which 3981 in intensive care. The active cases (i.e. the number of patients not yet recovered until that date) were 75,528. The forecast model estimated a number of infected persons for Italy of 234,000 about, and a duration of the epidemic of approximately 4 months.
Conclusions
One month after the first outbreaks there seemed to be the first signs of a decrease in the number of infections, showing that we could be now facing the descending phase of the epidemic. The forecast obtained thanks to our model could be used by decision-makers to implement coordinative and collaborative efforts in order to control the epidemic.
The pandemic due to novel Coronavirus must be a warning for all countries worldwide, regarding a rapid and complete dissemination of information, surveillance, health organization, and cooperation among the states.
Nickel (ii) complexes of A (1-16) Y10A and its smaller fragments including A (1-4), A (1-6), Ac-A (1-6) and Ac-A (8-16) Y10A have been studied by potentiometric, UV-Vis and circular dichroism spectroscopic measurements. The formation of mixed metal complexes and the distribution of metal ions among the possible coordination sites in the Cu (ii) -Ni (ii) -A (1- 16) Y10A and Cu (ii) -Ni (ii) -Zn (ii) -A (1-16) Y10A systems have also been evaluated. It was found that the hexadecapeptide and its fragments are effective nickel (ii) binding ligands and complex formation processes of nickel (ii) ions are quite similar to those of copper (ii). Formation of mono- and di-nuclear complexes was detected in the nickel (ii) -A (1-16) Y10A system suggesting the existence of two separated metal binding motifs: the N-terminus and internal histidyl residues. The preference for the coordination at the N-terminus was supported by the spectroscopic measurements but in equilibrium with the metal binding at the internal histidyl sites. Neither zinc (ii) nor nickel (ii) can, however, substitute copper (ii) in the mixed metal complexes of A (1-16) Y10A, but both metal ions are able to alter the distribution of copper (ii) ions among the various binding sites. Both N-terminus (amino and His6) and internal histidyl residues (His13 and His14) can work as dinuclear binding motifs, preferably accommodating copper (II) and zinc (II), respectively, while nickel (ii) can occupy the remaining free coordination sites. The Royal Society of Chemistry 2010
Jozsa E, Hosz K, Kallay C, De Bona P, Damante CA, Pappalardo G, Rizzarelli E, Sovago I
Dalton T (ISSN: 1477-9226, 1477-9234, 1477-9234electronic), 2010; 39(30): 7046-7053
G-quadruplexes are four-stranded DNA structures playing a key role in many biological functions and are promising for applications in the field of nanoelectronics. Characterizing the generation and fate of radical cations (electron holes) within these systems is important in relation to the DNA oxidative damage and/or conductivity issues. This study focuses on guanine radicals in G-quadruplexes formed by association of four TGGGGT strands in the presence of Na(+) cations, (TG4T)4/Na(+). Using nanosecond transient spectroscopy with 266 nm excitation, we quantitatively characterize hydrated ejected electrons and three types of guanine radicals. We show that, at an energy lower by 2.7 eV than the guanine ionization potential, one-photon ionization occurs with quantum yield of (3.5 +/- 0.5) x 10(-3). Deprotonation of the radical cations is completed within 20 mus, leading to the formation of (G-H2)(*) radicals, following a strongly nonexponential decay pattern. Within 10 ms, the latter undergoes tautomerization to deprotonated (G-H1)(*) radicals. The dynamics of the various radicals determined for (TG4T)4/Na(+), in connection to those reported previously for telomeric G-quadruplexes TEL21/Na(+), is correlated with energetic factors computed by quantum chemical methods. The faster deprotonation of radical cations in (TG4T)4/Na(+) compared to TEL21/Na(+) explains that irradiation of the former does not generate 8-oxodGuo, which is readily detected by high-performance liquid chromatography/mass spectrometry in the case of TEL21/Na(+).
Banyasz A, Balanikas E, Martinez-fernandez L, Baldacchino G, Douki T, Improta R, Markovitsi D
J Phys Chem B (ISSN: 1520-5207linking, 1520-6106), 2019 Jun 13; 123(23): 4950-4957
Atherosclerosis is characterized by intimal plaques of the arterial vessels that develop slowly and, in some cases, may undergo spontaneous rupture with subsequent heart attack or stroke. Currently, noninvasive diagnostic tools are inadequate to screen atherosclerotic lesions at high risk of acute complications. Therefore, the attention of the scientific community has been focused on the use of molecular imaging for identifying vulnerable plaques. Genetically engineered murine models such as ApoE(-/-) and ApoE(-/-)Fbn1C1039G(+/-) mice have been shown to be useful for testing new probes targeting biomarkers of relevant molecular processes for the characterization of vulnerable plaques, such as vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, intercellular adhesion molecule (ICAM)-1, P-selectin, and integrins, and for the potential development of translational tools to identify high-risk patients who could benefit from early therapeutic interventions. This review summarizes the main animal models of vulnerable plaques, with an emphasis on genetically altered mice, and the state-of-the-art preclinical molecular imaging strategies.
L'Istituto di Biostrutture e Bioimmagini (IBB) del Consiglio Nazionale delle Ricerche (CNR) ha 100 unità di personale distribuite nelle sedi di Napoli e Torino (70 ricercatori/tecnologi) e svolge attività di ricerca traslazionale per lo sviluppo nuovi strumenti per la prevenzione, la diagnosi e terapie a bersaglio molecolare.
Per realizzare questi obiettivi ricercatori che studiano le biomolecole da un punto di vista strutturale e funzionale collaborano con esperti di imaging preclinico che studiano modelli cellulari ed animali di malattie umane e ricercatori clinici che effettuano sperimentazioni nell'uomo.
Le attività di ricerca comprendono la ricerca di base, un laboratorio per l’Imaging preclinico dei piccoli animali da laboratorio ed aree di ricerca clinica svolte in collaborazione con Università ed altri enti di ricerca. La combinazione di competenze inerenti la chimica teorica e la progettazione e la sperimentazione, sia in vitro che in vivo, di nuovi agenti diagnostici e terapeutici con le competenze in molteplici modalità di imaging (tra cui MRI, imaging ottico, PET / SPECT, ecografia, TC) forniscono le basi interdisciplinari per realizzare una ricerca innovativa nel campo dell'imaging molecolare e della terapia personalizzata.
Un altro settore di ricerca sviluppato dall’IBB è rappresentato dall’e-Health. L’attività ha lo scopo di realizzare sistemi software open-source, costituiti da modelli, servizi e strumenti di supporto alla diagnosi, terapia e follow-up, nonché per la gestione innovativa dei processi sanitari.
L'Istituto fa parte del nodo italiano del Forum strategico europeo sulle infrastrutture di ricerca denominato EuroBioimaging (EuBi). EuBi è una large-scale facility a livello pan-europeo in grado di fornire a ricercatori provenienti da tutta Europa il libero accesso alle più innovative tecnologie di imaging biologico e medicale.
L’attività fondamentale dell’Istituto di Biostrutture e Bioimmagini è costituita dalle seguenti aree di ricerca:
• Design, sintesi, espressione e caratterizzazione strutturale di molecole di interesse biologico, e loro interazioni con ioni metallici. Applicazioni in campo diagnostico e terapeutico.
• Tecnologie biochimiche e biostrutture;
• Tecnologie biochimiche finalizzate alla diagnostica per immagini;
• Diagnostica per immagini e radioterapia;
• Imaging molecolare preclinico e clinico. Nuovi agenti diagnostici/teragnostici per Imaging Molecolare;
• Sviluppo di soluzioni tecnologiche innovative di e-health, con particolare attenzione alla tematiche della telemedicina e della diagnosi assistita.