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Biomedical subjects

Anna Maria Papini

Publications and source records attributed to Anna Maria Papini.

17 recordsLinked to original sources
PubMed2006

Conformation-activity relationship of designed glycopeptides as synthetic probes for the detection of autoantibodies, biomarkers of multiple sclerosis.

Sera from patients suffering from autoimmune disorders often contain multiple types of autoantibodies, some of which can be exclusive of a disease and thus used as biomarkers for diagnosis. Identification of these autoantibodies, as disease biomarkers, should be achieved using native antigens in simple biological assays. However, posttranslational modifications, such as glycosylation, may play a fundamental role for specific autoantibody recognition. In line with these observations, we described synthetic glycopeptides able to detect high autoantibody titers in sera of patients affected by multiple sclerosis, an inflammatory, demyelinating disease of the central nervous system. We describe here the conformation-activity relationship of a focused library of glycopeptides based on structural diversity, with the aim of defining the structural requirements for the interaction of these glycopeptide antigens with specific autoantibodies. The final goal is the optimization of an antigenic probe for multiple sclerosis, to be used in the development of a simple diagnostic test based on an immunoenzymatic assay. The reported results clearly indicate that glycopeptides able to reveal high antibody titers in multiple sclerosis sera are characterized by a type I' beta-turn around the minimal epitope Asn(Glc), which allows an efficient exposure of this moiety to antibodies interactions, in the context of a solid-phase immunoenzymatic assay.

Antigen-Antibody Reactions↗
PubMed2006

Hydration and hydrogen bonding of carbonyls in dimyristoyl-phosphatidylcholine bilayer.

We combine two-color ultrafast infrared spectroscopy and molecular dynamics simulation to investigate the hydration of carbonyl moieties in a dimyristoyl-phosphatidylcholine bilayer. Excitation with femtosecond infrared pulses of the OD stretching mode of heavy water produces a time dependent change of the absorption band of the phospholipid carbonyl groups. This intermolecular vibrational coupling affects the entire C=O band, thus suggesting that the optical inhomogeneity of the infrared response of carbonyl in phospholipid membranes cannot be attributed to the variance in hydration. Both the experimental and the theoretical results demonstrate that sn-1 carbonyl has a higher propensity to form hydrogen bonds with water in comparison to sn-2. The time-resolved experiment allows following the evolution of the system from a nonequilibrium localization of energy in the OD stretching mode to a thermally equilibrated condition and provides the characteristic time constants of the process. The approach opens a new opportunity for investigation of intermolecular structural relations in complex systems, like membranes, polymers, proteins, and glasses.

Journal Article↗
PubMed2006

Bradykinin antagonists modified with dipeptide mimetic beta-turn inducers.

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 beta-turn inducers.

Bradykinin↗
PubMed2006

Contribution of peptides to multiple sclerosis research.

Multiple sclerosis (MS) is an autoimmune disease associated with chronic inflammatory demyelination of the central nervous system in genetically susceptible individuals. Because of the disease complexity and heterogeneity, its pathogenesis remains unknown despite extensive research efforts, and specific effective treatments have not yet been developed. Peptide-based research has been important in attempts to unravel particular aspects of this complex disease, including the characterization of the different molecular mechanisms of MS, with the goal of providing useful products for immune-mediated therapies. In fact, in the past decade, peptide-based research has been predominant in research aimed to identify and/or develop target antigens as synthetic probes for specific biomarkers as well as innovative immunomodulating therapies. This review presents an overview of the contributions of peptide science to MS research and discusses future directions of peptide-based investigations.

Animals↗
PubMed2006

Development of antiviral fusion inhibitors: short modified peptides derived from the transmembrane glycoprotein of feline immunodeficiency virus.

Feline immunodeficiency virus (FIV) is a naturally occurring pathogen that causes an AIDS-like syndrome in domestic cats and is a valuable model system by which criteria for antiviral vaccines and drugs development can be tested. The cell-entry step of the lentivirus life cycle is regarded as a promising target for the development of new generation inhibitors. We have previously described potent in vitro anti-FIV activity associated with a synthetic octapeptide, termed C8 (Ac-Trp-Glu-Asp-Trp-Val-Gly-Trp-Ile-NH2), containing the Trp-rich motif of FIV transmembrane glycoprotein, which shares a common structural framework with the corresponding molecule of HIV and appears to play a similar role in cell entry. In this report, in an attempt to develop simpler potential fusion inhibitors to be tested in vivo, we describe further studies focused on synthetic peptide analogues of C8. Since C8 inhibitory activity is dependent upon the Trp motif, we systematically replaced these residues with bulky and/or aromatic natural and unnatural amino acids, in order to develop a rational structure-activity relationship. Furthermore, the amino acids located between the Trp residues, which are not crucial for inhibitory activity, were replaced by simple alkyl spacers of appropriate length. Design, NMR structural analysis, in vitro anti-FIV activity in lymphoid cell cultures, and serum stability of these new analogues are reported. The final results indicate that a simpler hexapeptide (Ac-Nal2-Ape-Nal2-Ape-Nal2-Ile-NH2; Nal2 = 3-naphthalen-2-yl-L-alanine, Ape = 5-aminopentanoic acid), almost entirely made up of unnatural amino acid residues, has markedly increased enzymatic stability, while maintaining strong antiviral potency in vitro.

Amino Acid Substitution↗
PubMed2006

Synthesis of stable analogues of geranylgeranyl diphosphate possessing a (Z,E,E)-geranylgeranyl side chain, docking analysis, and biological assays for prenyl protein transferase inhibition.

Herein, we report the synthesis of novel stable analogues of geranylgeranyl diphosphate (GGPP), in which the "natural" all-trans geranylgeranyl portion has been replaced by a (Z,E,E)-geranylgeranyl chain. The change in configuration and consequent change in the relative position of the polar portion with the lipophilic side chain did not improve the properties of the E,E,E analogues in their inhibition of geranylgeranyl protein transferase I (GGTase I). However, a significant level of GGTase I inhibition and selectivity for GGTase I over farnesyl transferase (FTase) was maintained the unsubstituted phosphonoacetamidoxy derivative 4 a. This has shed light on the relative importance of the configuration at the C2=C3 double bond among GGPP derivatives. Moreover, the biological activities of all the compounds reported herein, in particular the preferential FTase inhibitory activity shown by compound 6, were in good agreement with the results of docking analysis.

Dimethylallyltranstransferase↗
PubMed2006

Toward biomarkers in multiple sclerosis: new advances.

Multiple sclerosis is an autoimmune disease that commonly affects young adults. If initially characterized by acute relapses, it is later followed by only incomplete remission. Over years, progressive disability and irreversible deficit lead to chronic neurological deficits in the majority of patients. The clinical course is protracted and unpredictable, and no biological marker is useful in predicting the evolution of autoaggression and disability. It is difficult to diagnose and to monitor disease progression after the initial symptoms or even during the major clinical manifestations, and it is difficult to treat. In this review, the authors report recent advances in the field, focusing on the search of new antigens as a marker of the disease, in their relevance to the pathophysiology and diagnosis of the disease.

Biomarkers↗
PubMed2005

N-triazinylammonium tetrafluoroborates. A new generation of efficient coupling reagents useful for peptide synthesis.

A new generation of triazine-based coupling reagents (TBCRs), designed according to the concept of "superactive esters", was obtained by treatment of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium (DMTMM) chloride with lithium or silver tetrafluoroborate. The structure of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate was confirmed by X-ray diffraction. Activation of carboxylic acids by using this reagent proceeds via triazine "superactive ester". The coupling reagent was successfully used for the synthesis of Z-, Boc-, and Fmoc-protected dipeptides derived from natural and unnatural sterically hindered amino acids and for fragment condensation, in 80-100% yield and with high enantiomeric purity. The manual SPPS of the ACP(65-74) peptide fragment (H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-OH) proceeded significantly faster than with TBTU or HATU, as well as the automated SPPS of the same fragment gave a purer product than by using TBTU or PyBOP. The reagent was also demonstrated to be efficient in on-resin head-to-tail cyclization of constrained cyclopeptides, in SPPS synthesis of Aib peptides, and in the synthesis of esters from appropriate acids, alcohols, and phenols. The high efficiency and versatility of this new generation of TBCRs confirm, for the first time, the usefulness of the concept of "superactive esters" in rational design of the structure of coupling reagents.

Amides↗
PubMed2005

An N-glucosylated peptide detecting disease-specific autoantibodies, biomarkers of multiple sclerosis.

Multiple sclerosis (MS) is a complex disease that seems to depend on several pathophysiological processes. Because of its varied clinical presentation, natural history, and response to therapeutic interventions, MS can be considered to be a group of diseases that have not been yet characterized, thus resulting in difficult evaluation of prognosis. In the last few years, the role of autoAbs in MS has been reevaluated, and, therefore, their identification as specific biomarkers became a relevant target. In this paper, we demonstrate that an aberrant N-glucosylation is a fundamental determinant of autoAb recognition in MS. Thus, we developed CSF114(Glc), an antigenic probe accurately measuring IgM autoAbs in the sera of a patient population, as disease biomarker. The relevance of CSF114(Glc) is demonstrated by its clinical application and correlation with disease activity and prognosis. In fact, CSF114(Glc), a structure-based designed glycopeptide, is able to recognize, by ELISA, the presence of specific IgM autoAbs in the sera of a MS patient population but not in blood donors and other autoimmune conditions. AutoAbs specific for CSF114(Glc) isolated from MS patients recognized myelin and oligodendrocyte antigens by immunohistochemistry but not other nonrelevant tissues. We demonstrate that CSF114(Glc) is a reliable, specific probe in a longitudinal study of untreated MS patients. Development of IgG/IgM anti-CSF114(Glc) Abs paralleled clinical activity and brain lesions positive to MRI. Therefore, a CSF114(Glc)-based immunoassay on sera may have important prognostic value in monitoring MS disease progression guiding optimal therapeutic treatment.

Adult↗
PubMed2005

Synthesis of DEHP metabolites as biomarkers for GC-MS evaluation of phthalates as endocrine disrupters.

Phthalates are used primarily as plasticizers to make polyvinyl chloride (PVC) soft and flexible. In recent years the phthalate esters have attracted increasing attention as environmental and biomedical pollutants and, because of their toxicological characteristics. In particular, they are more and more recognized as endocrine disrupters. In this context, we describe herein an efficient synthetic pathway leading to a series of metabolites of di(2-ethylhexyl) phthalate (DEHP). Mono(2-ethylhexenyl) phthalate was used as starting material to obtain these products in good yield, large scale and GC-MS purity. The metabolites of DEHP were synthesized, for the first time, as biomarkers to verify their quantitative determination in human urine and serum by GC-MS analysis for studying the exposure to phthalates and establishing reference values.

Biomarkers↗
PubMed2005

The glycopeptide CSF114(Glc) detects serum antibodies in multiple sclerosis.

Synthetic glycopeptides have the potential to detect antibodies in multiple sclerosis (MS). In the present study, we analyzed the antibodies (IgM class, IgG class and IgG subclasses) to the synthetic glycopeptide CSF114(Glc) in the serum of 186 MS patients, 166 blood donors (BDs), 25 patients affected by meningitis/encephalitis, 41 affected by systemic lupus erythematosus (SLE) and 49 affected by rheumatoid arthritis (RA). The IgM antibody level to CSF114(Glc) was significantly increased in MS patients versus BDs (p<0.001) or versus other autoimmune diseases (SLE or RA, p<0.001). The IgG response was restricted to the subclass IgG2. IgM antibodies to CSF114(Glc) were found in 30% of relapsing/remitting MS patients and, at lower levels, in subjects affected by meningitis/encephalitis. The study of antibodies to CSF114(Glc) is a new, potential immunological marker of MS.

Adolescent↗
PubMed2005

Feline immunodeficiency virus plasma load reduction by a retroinverso octapeptide reproducing the Trp-rich motif of the transmembrane glycoprotein.

The Trp-rich motif (TrpM) of the transmembrane glycoprotein (TM) of lentiviruses is an attractive domain on which to design new potential cell entry peptide inhibitors. We recently demonstrated that an octapeptide reproducing the TrpM of feline immunodeficiency virus (FIV), designated C8, broadly inhibited this virus in vitro and that the retroinverso analogue of this peptide (riC8) was almost as inhibitory and exhibited features suggestive of a much increased stability. Here, we demonstrated that riC8 is indeed highly stable, maintaining its concentration unchanged for at least 24 h in cat serum in vitro. Furthermore, once inoculated into cats, riC8 produced no major acute toxic effects and exhibited satisfactory pharmacokinetic properties. Finally, we report the results of a short-term monotherapy experiment in chronically FIV-infected cats showing that riC8 is well tolerated and also has substantial antiviral activity in vivo. In particular, the mean viral load of riC8-treated animals declined progressively with increasing time of treatment, whereas that of control animals given C8 or solvent alone did not. These results provide the first evidence that clinically useful inhibition of virus replication with a small peptide derived from a functional domain of the TM of a lentivirus can be achieved in vivo.

Amino Acid Motifs↗
PubMed2003

A new biotin derivative-DOTA conjugate as a candidate for pretargeted diagnosis and therapy of tumors.

The synthesis of a new biotin derivative, the (CO) reduced N-aminohexyl biotinamido derivative, designed to be serum biotinidase resistant, and its conjugation to the chelator DOTA through an amide bond at one of the four carboxymethyl chains are described. The (90)Y-labeled conjugate was able to bind avidin at different Av/conjugate molar ratios with good results. The preclinical results indicate that this new biotin-DOTA conjugate is a good candidate for pretargeted diagnosis and therapy of tumors.

Antineoplastic Agents↗
PubMed2003

Synthetic peptides in the diagnosis of HIV infection.

Peptide-based enzyme-linked immunosorbent assays have been found to be enough sensitive and specific for the diagnosis of human immunodeficiency virus specific antibodies in acquired immunodeficiency syndrome patients. This review provides an overview of the most important peptides developed for use as synthetic antigens in immunodiagnosis of HIV-infected patients. In particular, many studies have been devoted to discriminate between the two retroviruses HIV-1 and HIV-2, as well as different subtypes.

AIDS Serodiagnosis↗
PubMed2002

Conformational and molecular modeling studies of sulfated cholecystokinin-15.

Conformational features of the C-terminal carboxyamidated pentadecapeptide of CCK (S(19)HRISDRD[SO(4)]-YMGWMDF(33)-NH(2)) were determined by NMR spectroscopy in a zwitterionic membrane-mimetic solvent system, composed of DPC micelles. The C-terminal octapeptide consisted of a well-defined pseudohelix that was nearly identical to the structure previously reported for nonsulfated CCK-8 in the same solvent system. N-terminal amino acids of CCK-15 were highly disordered, with no clear conformational preference. Extensive NOE-restrained molecular dynamics simulations of the CCK-15/CCK(1)-R complex suggested that almost all the experimentally determined intermolecular contact points provided by NMR, site-directed mutagenesis, and photoaffinity labeling could be simultaneously satisfied, when the N-terminus of the ligand is placed in close spatial proximity to the N-terminus of the receptor.

Amino Acid Sequence↗