Mario Scrima - Academia.edu (original) (raw)
Papers by Mario Scrima
Current topics in medicinal chemistry, Jan 24, 2016
Synthesis, computational study and biological evaluation of peptidomimetic analogues of FR235222 ... more Synthesis, computational study and biological evaluation of peptidomimetic analogues of FR235222 (3), a natural immunosuppressant and HDAC inhibitor, have been reported. These new compounds, bearing α-hydroxyketone moiety, as more stable zinc binding group (ZBG), were evaluated in vitro as HDAC inhibitors against the human HDACs isoforms 1-9 and in cellular antiproliferative assays on U937 human leukemia cell line. The 1,4-benzodiazepin-2,5-dione (BDZ), capping group and the natural ZBG, (S,R)-2-amino-9-hydroxy-8-oxodecanoic acid (Ahoda), were evaluated in order to probe HDAC inhibition and/or paralogue selectivity. Some of the new derivatives showed an interesting activity against a number of HDAC isozymes. The observed activity profile was rationalized by a computational assisted SAR study, in order to understand how the BDZ classes interact with the enzyme into the catalytic pocket. Despite its poor solubility, compound 17b showed significant antiproliferative profile and HDAC in...
Future Medicinal Chemistry, 2016
For long time Alzheimer's disease has been attributed to a cholinergic deficit. More rece... more For long time Alzheimer's disease has been attributed to a cholinergic deficit. More recently, it has been considered dependent on the accumulation of the amyloid beta peptide (Aβ), which promotes neuronal loss and impairs neuronal function. Results/methodology: In the present study, using biophysical and biochemical experiments we tested the hypothesis that in addition to its role as a neurotransmitter, acetylcholine may exert its action as an anti-Alzheimer agent through a direct interaction with Aβ. Our data provide evidence that acetylcholine favors the soluble peptide conformation and exerts a neuroprotective effect against the neuroinflammatory and toxic effects of Aβ. The present paper paves the way toward the development of new polyfunctional anti-Alzheimer therapeutics capable of intervening on both the cholinergic transmission and the Aβ aggregation.
Oxidative Medicine and Cellular Longevity, 2016
MicroRNAs are short (21-23 nucleotides), noncoding RNAs that typically silence posttranscriptiona... more MicroRNAs are short (21-23 nucleotides), noncoding RNAs that typically silence posttranscriptional gene expression through interaction with target messenger RNAs. Currently, miRNAs have been identified in almost all studied multicellular eukaryotes in the plant and animal kingdoms. Additionally, recent studies reported that miRNAs can also be encoded by certain single-cell eukaryotes and by viruses. The vast majority of viral miRNAs are encoded by the herpesviruses family. These DNA viruses including Epstein-Barr virus encode their own miRNAs and/or manipulate the expression of cellular miRNAs to facilitate respective infection cycles. Modulation of the control pathways of miRNAs expression is often involved in the promotion of tumorigenesis through a specific cascade of transduction signals. Notably, latent infection with Epstein-Barr virus is considered liable of causing several types of malignancies, including the majority of gastric carcinoma cases detected worldwide. In this review, we describe the role of the Epstein-Barr virus in gastric carcinogenesis, summarizing the functions of the Epstein-Barr virus-encoded viral proteins and related epigenetic alterations as well as the roles of Epstein-Barr virus-encoded and virally modulated cellular miRNAs.
Bioorganic & Medicinal Chemistry Letters, 2006
Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide ... more Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic b-turn inducers.
![Research paper thumbnail of A New Series of 1,3-Dihidro-Imidazo[1,5- c ]thiazole-5,7-Dione Derivatives: Synthesis and Interaction with Aβ(25-35) Amyloid Peptide](https://attachments.academia-assets.com/45670206/thumbnails/1.jpg)
](Chemical Biology & Drug Design, 2009
European Journal of Medicinal Chemistry, 2012
Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited... more Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited number of them are effective antifungal drugs, devoid of toxic and undesirable side effects. Furthermore, resistance development and fungistatic rather than fungicidal activities represent limitations of current antifungal therapy. Therefore an urgent need for a new generation of antifungal agents remains. We recently synthesised a set of linear and cyclic peptides characterized by sequences typical of membrane-active antimicrobial peptides (AMP). AMT2, cyclo-AMT2, AMT3 and cyclo-AMT3 (Scheme 1) were tested against different yeast species and exhibited general antifungal activity, with a specificity against Cryptococcus neoformans. To evaluate the role of the membrane cell in the mechanism of antifungal activity, we investigated the conformational behaviour of AMT2, cyclo-AMT2, AMT3 and cyclo-AMT3 in different bio-membrane mimicking systems using a combined approach based on spectroscopy and microscopy techniques. Our data highlight the behaviour of the peptides to interact with the bilayer surface, excluding their ability to destabilize or permeabilize the fungal cell wall. Microbial membrane, indeed, may be an important platform for specific interactions of peptides with specific targets involved in the cell wall synthesis.
![Research paper thumbnail of 1,4-Disubstituted-[1,2,3]triazolyl-Containing Analogues of MT-II: Design, Synthesis, Conformational Analysis, and Biological Activity](https://attachments.academia-assets.com/38376010/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, 2014
Chemical Biology & Drug Design, 2007
In the attempt to identify a new lead compound able to modify the conformational preferences of t... more In the attempt to identify a new lead compound able to modify the conformational preferences of the b-amyloid peptides, a set of new compounds characterized by a thiazolidine ring linked to several different aryl moieties were synthesized. The ability of these compounds to prevent the b-amyloid aggregation was evaluated using circular dichroism and nuclear magnetic resonance techniques. Molecular docking procedure allowed an interpretation of spectroscopic in the key of molecular interaction.
The Journal of Physical Chemistry B, 2010
The native environment for membrane proteins is the highly asymmetric phospholipid bilayer, and t... more The native environment for membrane proteins is the highly asymmetric phospholipid bilayer, and this has a large effect on both their structure and dynamics. Reproducing this environment in samples suitable for spectroscopic and diffraction experiments is a key issue, and flexibility in sample preparation is essential to accommodate the diverse size, shape, and other physical properties of membrane proteins. In most cases, to ensure that the biological activities are maintained, this means reconstituting the proteins in fully hydrated planar phospholipid bilayers. The asymmetric character of protein-containing bilayers means that it is possible to prepare either oriented or unoriented (powder) samples. Here we demonstrate the equivalence of mechanical, magnetic, and what we refer to as "rotational alignment" of membrane proteins in phospholipid bilayer samples for solid-state NMR spectroscopy. The trans-membrane domain of virus protein "u" (Vpu) from human immunodeficiency virus (HIV-1) and the full-length membrane-bound form of fd bacteriophage coat protein in phospholipid bilayers are used as examples. The equivalence of structural constraints from oriented and unoriented (powder) samples of membrane proteins is based on two concepts: (1) their alignment is defined by the direction of the bilayer normal relative to the magnetic field and (2) they undergo rapid rotational diffusion about the same bilayer normal in liquid crystalline membranes. The measurement of angular constraints relative to a common external axis system defined by the bilayer normal for all sites in the protein is an essential element of oriented sample (OS) solid-state NMR.
Clinical and Vaccine Immunology, 2007
The immunogenicity of a lipoylated peptide (lipo-P59) reproducing the membrane-proximal external ... more The immunogenicity of a lipoylated peptide (lipo-P59) reproducing the membrane-proximal external region (MPER) of the transmembrane glycoprotein of feline immunodeficiency virus (FIV) was investigated with cats. In the attempt to mimic the context in which MPER is located within intact virions, lipo-P59 was administered in association with membrane-like micelles. Analyses showed that in this milieu, lipo-P59 had a remarkable propensity
Introduction which share the ability to deliver therapeutic agents (proteins, oligonucleotides) i... more Introduction which share the ability to deliver therapeutic agents (proteins, oligonucleotides) into target cells. The mechanisms proposed for the CPPs cellular uptake (endocytic, endosomal escape, etc.) are still controversial. In the hypothesis that membrane lateral heterogeneity generated by multi lipid and protein components in cell membrane could play an important role in CPPs translocation process, we conducted studies on two popular CPPs, penetratin (RQIKIWFQNRRMKWKK)[1] and pep-1 ( ...
The Journal of Physical Chemistry B, 2013
The effects of stacking interactions on the oxidation potentials of single strand oligonucleotide... more The effects of stacking interactions on the oxidation potentials of single strand oligonucleotides containing up to four consecutive adenines, alternated with thymines and cytosines in different sequences and ratios, have been determined by means of differential pulse voltammetry. Voltammetric measurements point toward the establishment in solution of structured oligonucleotide conformations, in which the nucleobases are well stacked altogether. Molecular dynamics simulations confirm that finding, indicating that single strands assume geometrical parameters characteristic of the B-DNA form. The analysis of the voltammetric signals in terms of a simple effective tight binding quantum model leads one to infer a robust set of parameters for treating hole transfer in one-electron-oxidized DNA containing adenines and thymines.
Journal of Medicinal Chemistry, 2014
N6-isopentenyladenosine (i6A), a modified nucleoside belonging to the cytokinin family, has shown... more N6-isopentenyladenosine (i6A), a modified nucleoside belonging to the cytokinin family, has shown in humans many biological actions, including antitumoral effects through the modulation of the farnesyl pyrophosphate synthase (FPPS) activity. To investigate the relationship between i6A and FPPS, we undertook an inverse virtual screening computational target searching, testing i6A on a large panel of 3D protein structures involved in cancer processes. Experimentally, we performed an NMR investigation of i6A in the presence of FPPS protein. Both inverse virtual screening and saturation transfer difference (STD) NMR outcomes provided evidence of the structural interaction between i6A and FPPS, pointing to i6A as a valuable lead compound in the search of new ligands endowed with antitumoral potential and targeting FPPS protein. Figure 1. Chemical structure of i6A (a), zoledronic acid (b), and FPPS allosteric ligand 7 (c).
Scientific reports, 2015
Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of se... more Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal...
PLoS ONE, 2014
b amyloid peptide plays an important role in both the manifestation and progression of Alzheimer ... more b amyloid peptide plays an important role in both the manifestation and progression of Alzheimer disease. It has a tendency to aggregate, forming low-molecular weight soluble oligomers, higher-molecular weight protofibrillar oligomers and insoluble fibrils. The relative importance of these single oligomeric-polymeric species, in relation to the morbidity of the disease, is currently being debated. Here we present an Atomic Force Microscopy (AFM) study of Ab(25-35) aggregation on hydrophobic dioleoylphosphatidylcholine (DOPC) and DOPC/docosahexaenoic 22:6 acid (DHA) lipid bilayers. Ab(25-35) is the smallest fragment retaining the biological activity of the full-length peptide, whereas DOPC and DOPC/DHA lipid bilayers were selected as models of cell-membrane environments characterized by different fluidity. Our results provide evidence that in hydrophobic DOPC and DOPC/DHA lipid bilayers, Ab(25-35) forms layered aggregates composed of mainly annular structures. The mutual interaction between annular structures and lipid surfaces end-results into a membrane solubilization. The presence of DHA as a membrane-fluidizing agent is essential to protect the membrane from damage caused by interactions with peptide aggregates; to reduces the bilayer defects where the delipidation process starts. OPEN ACCESS Citation: Sublimi Saponetti M, Grimaldi M, Scrima M, Albonetti C, Nori SL, et al. (2014) Aggregation of Aß(25-35) on DOPC and DOPC/DHA Bilayers: An Atomic Force Microscopy Study. PLoS ONE 9(12): e115780.
The Journal of Physical Chemistry B, 2015
Differential pulse voltammetries of guanine-rich single- and double-stranded oligonucleotides con... more Differential pulse voltammetries of guanine-rich single- and double-stranded oligonucleotides containing up to six consecutive guanines are reported. The observed progressive lowering of the first voltammetric peak potential as the number of adjacent guanines increases unambiguously points toward the establishment of delocalized hole domains; the hole stabilization energy is ca. 0.1 eV per GG step, significantly lower than that observed for AA steps.
![Research paper thumbnail of A New Series of 1,3-Dihidro-Imidazo[1,5- c ]thiazole-5,7-Dione Derivatives: Synthesis and Interaction with Aβ(25-35) Amyloid Peptide](https://attachments.academia-assets.com/45644563/thumbnails/1.jpg)
](Chemical Biology & Drug Design, 2009
Deposition of senile plaques composed of fibrillar aggregates of Ab-amyloid peptide is a characte... more Deposition of senile plaques composed of fibrillar aggregates of Ab-amyloid peptide is a characteristic hallmark of Alzheimer's disease. A widely employed approach in the study of anti-Alzheimer agents involves the identification of substances able to prevent amyloid aggregation, or to disaggregate the amyloid fibrils through a direct structural interaction with the soluble or aggregated forms of the peptide. Here, we report the synthesis of a set of 1,3-dihydro-3,6-disubstitutedimidazo[1,5-c]thiazole-5,7-dione derivatives supporting different alkyl, aryl and alkylamine side chains. The ability of these compounds to interact with the Ab(25-35) peptide was evaluated using circular dichroism, nuclear magnetic resonance and thioflavin fluorescence spectroscopy. A molecular model for Ab(25-35)-ligand interactions was calculated by molecular docking procedures. Our data show that the ability of the synthesized compounds to modify the structural behaviour of Ab(25-35) varies as a function of the overall structural features of the ligands rather contributions from specific individual substituents.
Bioorganic & Medicinal Chemistry, 2010
Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited... more Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited number of them are effective antifungal drugs, devoid of toxic and undesirable side effects. Furthermore, resistance development and fungistatic rather than fungicidal activities represent limitations of current antifungal therapy. Therefore there remains an urgent need for a new generation of antifungal agents.
Journal of Medicinal Chemistry, 2012
We previously reported that CSF114(Glc) detects diagnostic autoantibodies in multiple sclerosis s... more We previously reported that CSF114(Glc) detects diagnostic autoantibodies in multiple sclerosis sera. We report herein a bioinformatic analysis of myelin proteins and CSF114(Glc), which led to the identification of five sequences. These glucopeptides were synthesized and tested in enzymatic assays, showing a common minimal epitope. Starting from that, we designed an optimized sequence, SP077, showing a higher homology with both CSF114(Glc) and the five sequences selected using the bioinformatic approach. SP077 was synthesized and tested on 50 multiple sclerosis patients' sera, and was able to detect higher antibody titers as compared to CSF114(Glc). Finally, the conformational properties of SP077 were studied by NMR spectroscopy and structure calculations. Thus, the immunological activity of SP077 in the recognition of specific autoantibodies in multiple sclerosis patients' sera may be ascribed to both the optimized design of its epitopic region and the superior surface interacting properties of its C-terminal region.
Journal of Peptide Science, 2006
The accumulation of β-amyloid peptides into senile plaques is one of the hallmarks of Alzheimer's... more The accumulation of β-amyloid peptides into senile plaques is one of the hallmarks of Alzheimer's disease (AD). There is mounting evidence that the lipid matrix of neuronal cell membranes plays an important role in the β-sheet oligomerization process of β-amyloid. Aβ(25-35), the sequence of which is GSNKGAIIGLM, is a highly toxic segment of amyloid β (Aβ)-peptides, which forms fibrillary aggregates. In the present work, two spin-labelled Aβ(25-35) analogues containing the nitroxide group of the amino acid TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) as a paramagnetic probe at the N -or the C-terminus of the peptide sequence, respectively, were synthesized in order to investigate the peptide-membrane interaction. The orientation and associated changes of the peptide conformation in the presence of different artificial membrane models (micelles, liposomes) were evaluated by electron paramagnetic resonance and circular dichroism techniques. The results of this study allowed us to propose a model in which the C-terminal portion of the peptide is highly associated to the membrane, while the N -terminal part extends into the aqueous phase with occasional contacts with the lipid head-group region. Interestingly, the interaction of the C-terminal portion of the peptide is particularly enhanced in the presence of sodium dodecyl sulfate (SDS) molecules.
Current topics in medicinal chemistry, Jan 24, 2016
Synthesis, computational study and biological evaluation of peptidomimetic analogues of FR235222 ... more Synthesis, computational study and biological evaluation of peptidomimetic analogues of FR235222 (3), a natural immunosuppressant and HDAC inhibitor, have been reported. These new compounds, bearing α-hydroxyketone moiety, as more stable zinc binding group (ZBG), were evaluated in vitro as HDAC inhibitors against the human HDACs isoforms 1-9 and in cellular antiproliferative assays on U937 human leukemia cell line. The 1,4-benzodiazepin-2,5-dione (BDZ), capping group and the natural ZBG, (S,R)-2-amino-9-hydroxy-8-oxodecanoic acid (Ahoda), were evaluated in order to probe HDAC inhibition and/or paralogue selectivity. Some of the new derivatives showed an interesting activity against a number of HDAC isozymes. The observed activity profile was rationalized by a computational assisted SAR study, in order to understand how the BDZ classes interact with the enzyme into the catalytic pocket. Despite its poor solubility, compound 17b showed significant antiproliferative profile and HDAC in...
Future Medicinal Chemistry, 2016
For long time Alzheimer's disease has been attributed to a cholinergic deficit. More rece... more For long time Alzheimer's disease has been attributed to a cholinergic deficit. More recently, it has been considered dependent on the accumulation of the amyloid beta peptide (Aβ), which promotes neuronal loss and impairs neuronal function. Results/methodology: In the present study, using biophysical and biochemical experiments we tested the hypothesis that in addition to its role as a neurotransmitter, acetylcholine may exert its action as an anti-Alzheimer agent through a direct interaction with Aβ. Our data provide evidence that acetylcholine favors the soluble peptide conformation and exerts a neuroprotective effect against the neuroinflammatory and toxic effects of Aβ. The present paper paves the way toward the development of new polyfunctional anti-Alzheimer therapeutics capable of intervening on both the cholinergic transmission and the Aβ aggregation.
Oxidative Medicine and Cellular Longevity, 2016
MicroRNAs are short (21-23 nucleotides), noncoding RNAs that typically silence posttranscriptiona... more MicroRNAs are short (21-23 nucleotides), noncoding RNAs that typically silence posttranscriptional gene expression through interaction with target messenger RNAs. Currently, miRNAs have been identified in almost all studied multicellular eukaryotes in the plant and animal kingdoms. Additionally, recent studies reported that miRNAs can also be encoded by certain single-cell eukaryotes and by viruses. The vast majority of viral miRNAs are encoded by the herpesviruses family. These DNA viruses including Epstein-Barr virus encode their own miRNAs and/or manipulate the expression of cellular miRNAs to facilitate respective infection cycles. Modulation of the control pathways of miRNAs expression is often involved in the promotion of tumorigenesis through a specific cascade of transduction signals. Notably, latent infection with Epstein-Barr virus is considered liable of causing several types of malignancies, including the majority of gastric carcinoma cases detected worldwide. In this review, we describe the role of the Epstein-Barr virus in gastric carcinogenesis, summarizing the functions of the Epstein-Barr virus-encoded viral proteins and related epigenetic alterations as well as the roles of Epstein-Barr virus-encoded and virally modulated cellular miRNAs.
Bioorganic & Medicinal Chemistry Letters, 2006
Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide ... more Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic b-turn inducers.
Chemical Biology & Drug Design, 2009
European Journal of Medicinal Chemistry, 2012
Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited... more Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited number of them are effective antifungal drugs, devoid of toxic and undesirable side effects. Furthermore, resistance development and fungistatic rather than fungicidal activities represent limitations of current antifungal therapy. Therefore an urgent need for a new generation of antifungal agents remains. We recently synthesised a set of linear and cyclic peptides characterized by sequences typical of membrane-active antimicrobial peptides (AMP). AMT2, cyclo-AMT2, AMT3 and cyclo-AMT3 (Scheme 1) were tested against different yeast species and exhibited general antifungal activity, with a specificity against Cryptococcus neoformans. To evaluate the role of the membrane cell in the mechanism of antifungal activity, we investigated the conformational behaviour of AMT2, cyclo-AMT2, AMT3 and cyclo-AMT3 in different bio-membrane mimicking systems using a combined approach based on spectroscopy and microscopy techniques. Our data highlight the behaviour of the peptides to interact with the bilayer surface, excluding their ability to destabilize or permeabilize the fungal cell wall. Microbial membrane, indeed, may be an important platform for specific interactions of peptides with specific targets involved in the cell wall synthesis.
Journal of Medicinal Chemistry, 2014
Chemical Biology & Drug Design, 2007
In the attempt to identify a new lead compound able to modify the conformational preferences of t... more In the attempt to identify a new lead compound able to modify the conformational preferences of the b-amyloid peptides, a set of new compounds characterized by a thiazolidine ring linked to several different aryl moieties were synthesized. The ability of these compounds to prevent the b-amyloid aggregation was evaluated using circular dichroism and nuclear magnetic resonance techniques. Molecular docking procedure allowed an interpretation of spectroscopic in the key of molecular interaction.
The Journal of Physical Chemistry B, 2010
The native environment for membrane proteins is the highly asymmetric phospholipid bilayer, and t... more The native environment for membrane proteins is the highly asymmetric phospholipid bilayer, and this has a large effect on both their structure and dynamics. Reproducing this environment in samples suitable for spectroscopic and diffraction experiments is a key issue, and flexibility in sample preparation is essential to accommodate the diverse size, shape, and other physical properties of membrane proteins. In most cases, to ensure that the biological activities are maintained, this means reconstituting the proteins in fully hydrated planar phospholipid bilayers. The asymmetric character of protein-containing bilayers means that it is possible to prepare either oriented or unoriented (powder) samples. Here we demonstrate the equivalence of mechanical, magnetic, and what we refer to as "rotational alignment" of membrane proteins in phospholipid bilayer samples for solid-state NMR spectroscopy. The trans-membrane domain of virus protein "u" (Vpu) from human immunodeficiency virus (HIV-1) and the full-length membrane-bound form of fd bacteriophage coat protein in phospholipid bilayers are used as examples. The equivalence of structural constraints from oriented and unoriented (powder) samples of membrane proteins is based on two concepts: (1) their alignment is defined by the direction of the bilayer normal relative to the magnetic field and (2) they undergo rapid rotational diffusion about the same bilayer normal in liquid crystalline membranes. The measurement of angular constraints relative to a common external axis system defined by the bilayer normal for all sites in the protein is an essential element of oriented sample (OS) solid-state NMR.
Clinical and Vaccine Immunology, 2007
The immunogenicity of a lipoylated peptide (lipo-P59) reproducing the membrane-proximal external ... more The immunogenicity of a lipoylated peptide (lipo-P59) reproducing the membrane-proximal external region (MPER) of the transmembrane glycoprotein of feline immunodeficiency virus (FIV) was investigated with cats. In the attempt to mimic the context in which MPER is located within intact virions, lipo-P59 was administered in association with membrane-like micelles. Analyses showed that in this milieu, lipo-P59 had a remarkable propensity
Introduction which share the ability to deliver therapeutic agents (proteins, oligonucleotides) i... more Introduction which share the ability to deliver therapeutic agents (proteins, oligonucleotides) into target cells. The mechanisms proposed for the CPPs cellular uptake (endocytic, endosomal escape, etc.) are still controversial. In the hypothesis that membrane lateral heterogeneity generated by multi lipid and protein components in cell membrane could play an important role in CPPs translocation process, we conducted studies on two popular CPPs, penetratin (RQIKIWFQNRRMKWKK)[1] and pep-1 ( ...
The Journal of Physical Chemistry B, 2013
The effects of stacking interactions on the oxidation potentials of single strand oligonucleotide... more The effects of stacking interactions on the oxidation potentials of single strand oligonucleotides containing up to four consecutive adenines, alternated with thymines and cytosines in different sequences and ratios, have been determined by means of differential pulse voltammetry. Voltammetric measurements point toward the establishment in solution of structured oligonucleotide conformations, in which the nucleobases are well stacked altogether. Molecular dynamics simulations confirm that finding, indicating that single strands assume geometrical parameters characteristic of the B-DNA form. The analysis of the voltammetric signals in terms of a simple effective tight binding quantum model leads one to infer a robust set of parameters for treating hole transfer in one-electron-oxidized DNA containing adenines and thymines.
Journal of Medicinal Chemistry, 2014
N6-isopentenyladenosine (i6A), a modified nucleoside belonging to the cytokinin family, has shown... more N6-isopentenyladenosine (i6A), a modified nucleoside belonging to the cytokinin family, has shown in humans many biological actions, including antitumoral effects through the modulation of the farnesyl pyrophosphate synthase (FPPS) activity. To investigate the relationship between i6A and FPPS, we undertook an inverse virtual screening computational target searching, testing i6A on a large panel of 3D protein structures involved in cancer processes. Experimentally, we performed an NMR investigation of i6A in the presence of FPPS protein. Both inverse virtual screening and saturation transfer difference (STD) NMR outcomes provided evidence of the structural interaction between i6A and FPPS, pointing to i6A as a valuable lead compound in the search of new ligands endowed with antitumoral potential and targeting FPPS protein. Figure 1. Chemical structure of i6A (a), zoledronic acid (b), and FPPS allosteric ligand 7 (c).
Scientific reports, 2015
Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of se... more Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a α-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal...
PLoS ONE, 2014
b amyloid peptide plays an important role in both the manifestation and progression of Alzheimer ... more b amyloid peptide plays an important role in both the manifestation and progression of Alzheimer disease. It has a tendency to aggregate, forming low-molecular weight soluble oligomers, higher-molecular weight protofibrillar oligomers and insoluble fibrils. The relative importance of these single oligomeric-polymeric species, in relation to the morbidity of the disease, is currently being debated. Here we present an Atomic Force Microscopy (AFM) study of Ab(25-35) aggregation on hydrophobic dioleoylphosphatidylcholine (DOPC) and DOPC/docosahexaenoic 22:6 acid (DHA) lipid bilayers. Ab(25-35) is the smallest fragment retaining the biological activity of the full-length peptide, whereas DOPC and DOPC/DHA lipid bilayers were selected as models of cell-membrane environments characterized by different fluidity. Our results provide evidence that in hydrophobic DOPC and DOPC/DHA lipid bilayers, Ab(25-35) forms layered aggregates composed of mainly annular structures. The mutual interaction between annular structures and lipid surfaces end-results into a membrane solubilization. The presence of DHA as a membrane-fluidizing agent is essential to protect the membrane from damage caused by interactions with peptide aggregates; to reduces the bilayer defects where the delipidation process starts. OPEN ACCESS Citation: Sublimi Saponetti M, Grimaldi M, Scrima M, Albonetti C, Nori SL, et al. (2014) Aggregation of Aß(25-35) on DOPC and DOPC/DHA Bilayers: An Atomic Force Microscopy Study. PLoS ONE 9(12): e115780.
The Journal of Physical Chemistry B, 2015
Differential pulse voltammetries of guanine-rich single- and double-stranded oligonucleotides con... more Differential pulse voltammetries of guanine-rich single- and double-stranded oligonucleotides containing up to six consecutive guanines are reported. The observed progressive lowering of the first voltammetric peak potential as the number of adjacent guanines increases unambiguously points toward the establishment of delocalized hole domains; the hole stabilization energy is ca. 0.1 eV per GG step, significantly lower than that observed for AA steps.
Chemical Biology & Drug Design, 2009
Deposition of senile plaques composed of fibrillar aggregates of Ab-amyloid peptide is a characte... more Deposition of senile plaques composed of fibrillar aggregates of Ab-amyloid peptide is a characteristic hallmark of Alzheimer's disease. A widely employed approach in the study of anti-Alzheimer agents involves the identification of substances able to prevent amyloid aggregation, or to disaggregate the amyloid fibrils through a direct structural interaction with the soluble or aggregated forms of the peptide. Here, we report the synthesis of a set of 1,3-dihydro-3,6-disubstitutedimidazo[1,5-c]thiazole-5,7-dione derivatives supporting different alkyl, aryl and alkylamine side chains. The ability of these compounds to interact with the Ab(25-35) peptide was evaluated using circular dichroism, nuclear magnetic resonance and thioflavin fluorescence spectroscopy. A molecular model for Ab(25-35)-ligand interactions was calculated by molecular docking procedures. Our data show that the ability of the synthesized compounds to modify the structural behaviour of Ab(25-35) varies as a function of the overall structural features of the ligands rather contributions from specific individual substituents.
Bioorganic & Medicinal Chemistry, 2010
Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited... more Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited number of them are effective antifungal drugs, devoid of toxic and undesirable side effects. Furthermore, resistance development and fungistatic rather than fungicidal activities represent limitations of current antifungal therapy. Therefore there remains an urgent need for a new generation of antifungal agents.
Journal of Medicinal Chemistry, 2012
We previously reported that CSF114(Glc) detects diagnostic autoantibodies in multiple sclerosis s... more We previously reported that CSF114(Glc) detects diagnostic autoantibodies in multiple sclerosis sera. We report herein a bioinformatic analysis of myelin proteins and CSF114(Glc), which led to the identification of five sequences. These glucopeptides were synthesized and tested in enzymatic assays, showing a common minimal epitope. Starting from that, we designed an optimized sequence, SP077, showing a higher homology with both CSF114(Glc) and the five sequences selected using the bioinformatic approach. SP077 was synthesized and tested on 50 multiple sclerosis patients' sera, and was able to detect higher antibody titers as compared to CSF114(Glc). Finally, the conformational properties of SP077 were studied by NMR spectroscopy and structure calculations. Thus, the immunological activity of SP077 in the recognition of specific autoantibodies in multiple sclerosis patients' sera may be ascribed to both the optimized design of its epitopic region and the superior surface interacting properties of its C-terminal region.
Journal of Peptide Science, 2006
The accumulation of β-amyloid peptides into senile plaques is one of the hallmarks of Alzheimer's... more The accumulation of β-amyloid peptides into senile plaques is one of the hallmarks of Alzheimer's disease (AD). There is mounting evidence that the lipid matrix of neuronal cell membranes plays an important role in the β-sheet oligomerization process of β-amyloid. Aβ(25-35), the sequence of which is GSNKGAIIGLM, is a highly toxic segment of amyloid β (Aβ)-peptides, which forms fibrillary aggregates. In the present work, two spin-labelled Aβ(25-35) analogues containing the nitroxide group of the amino acid TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) as a paramagnetic probe at the N -or the C-terminus of the peptide sequence, respectively, were synthesized in order to investigate the peptide-membrane interaction. The orientation and associated changes of the peptide conformation in the presence of different artificial membrane models (micelles, liposomes) were evaluated by electron paramagnetic resonance and circular dichroism techniques. The results of this study allowed us to propose a model in which the C-terminal portion of the peptide is highly associated to the membrane, while the N -terminal part extends into the aqueous phase with occasional contacts with the lipid head-group region. Interestingly, the interaction of the C-terminal portion of the peptide is particularly enhanced in the presence of sodium dodecyl sulfate (SDS) molecules.