free-radicals-chemical-biology-from-chemical-behavior-to-biomarker

Free Radicals in Chemical Biology: from Chemical Behavior to Biomarker Development

The involvement of free radicals in life sciences has constantly increased with time and has been connected to several physiological and pathological ...

A series of new beta-peptido sulfonamides, related to the chemotactic tripeptide fMLF-OMe, has been synthesized. The examined 1a,b-7a,b models contain the achiral -HN-(CH(2))(2)-SO(2)- taurine (Tau) residue or the chiral -HN-CH(nBu)-CH(2)-SO(2)- and -HN-CH(iBu)-CH(2)-SO(2)- residues, corresponding to the beta-aminocarboxylic acid counterparts beta(3)-HNle and beta(3)-HLeu, respectively. The biological activity of the new analogues has been determined on human neutrophils and compared with that of the reference ligand as well as that of the previously studied related models. The results are analyzed in terms of structure-activity relationships. The conformational preferences of the new tripeptides 1b and 2b, containing a central chiral beta-amino-ethanesulfonic acid residue, have also been discussed.

Beta-peptido sulfonamides: for-Met-Leu-Phe-OMe analogues containing taurine and chiral beta-amino-ethanesulfonic acid residues.

In order to gain information on the activity shown by alpha-peptide/beta-sulfonamidopeptide hybrid analogs of the potent chemotactic agent fMLF-OMe, a structure-activity study is reported on N-Boc- and N-formyl tripeptide models containing an aminoalkanesulfonic acid as central residue. Directed migration (chemotaxis), superoxide anion production, and lysozyme release have been measured. The biochemical functions and the conformational properties of the new compounds are discussed and related to previously studied models containing beta-residues.

Alpha-peptide/beta-sulfonamidopeptide hybrids: analogs of the chemotactic agent for-Met-Leu-Phe-OMe.

The aim of this pilot study was to analyze the effects of glucosamine (GlcN) and its N-acetyl-phenylalanine derivative (NAPA) in Vitamin A model of osteoarthritis (OA) in rabbits. GlcN or NAPA or saline solution was intra-articularly administered in rabbit OA knees. Histological analysis revealed that treatment with GlcN or NAPA was associated with more homogeneous chondrocyte cellularity, absence of fissures and fragmentation and more intense staining of the matrix with Alcian Blue compared to the articular surfaces of the knees treated with saline solution. Comparative in vitro study performed on rabbit primary chondrocytes revealed that GlcN and NAPA were also able to counteract the IL-1beta-upregulation of genes coding for metalloproteases and inflammatory cytokines. Our preliminary in vivo and in vitro studies suggest that GlcN and NAPA could play a disease-modifying protective role in OA by an anti-catabolic effect and an anti-inflammatory activity on chondrocytes.

Effects of intra-articular administration of glucosamine and a peptidyl-glucosamine derivative in a rabbit model of experimental osteoarthritis: a pilot study.

Peptide derivatives 1-5, incorporating synthetic non-proteinogenic amino acids, related to the beta-amyloid 17-21 fragment of the amyloidogenic Abeta(1-40), and the N-protected decapeptide 6, corresponding to a dimeric sequence of the same fragment, have been synthesized. These compounds were designed by using Soto's pentapeptide Ac-LPFFD-NH(2) (iAbeta5p) as lead compound. Their activity as inhibitors of fibrillogenesis and stability against enzymatic degradation have been determined. Compounds 1, 5 and 6 are potent inhibitors in comparison to the lead compound. Exposure to chymotrypsin of peptide derivatives 1-5, all containing unnatural amino acids, shows increased stability as compared with iAbeta5p and 6. Conformational properties of the new compounds have been determined by CD and FT-IR spectroscopies.

Synthesis and activity of fibrillogenesis peptide inhibitors related to the 17-21 beta-amyloid sequence.

A small library of N-For and N-Boc tetrapeptidic analogues of the chemotactic tripeptide For-Met-Leu-Phe-OMe (fMLF-OMe), obtained by incorporating three different spacer aminoacids (Gly, betaAla and Pro) between the native residues of Met and Leu (N-For- and N-Boc-Met-Xaa-Leu-Phe-OMe; Xaa2 series) and Leu and Phe (N-For- and N-Boc-Met-Leu-Xaa-Phe-OMe; Xaa3 series), have been synthesized and examined for their biological activity as agonists and antagonists. Chemotaxis, lysozyme release and superoxide anion production have been measured. All the N-For analogues maintain good to moderate chemotactic activity with the betaAla3 15 model reaching the maximum value. All the N-Boc tetrapeptides are efficient chemotactic antagonists. Conversely, with the exception of the moderate antagonistic activity exhibited by the N-Boc Xaa2 models against lysozyme release, all the other N-Boc analogues do not show significant activity against both superoxide anion and lysozyme release.

Synthesis and bioactivity of chemotactic tetrapeptides: fMLF-OMe analogues incorporating spacer aminoacids at the lateral positions.

New potent indolylarylsulfone (IAS) HIV-1 NNRTIs were obtained by coupling natural and unnatural amino acids to the 2-carboxamide and introducing different electron-withdrawing substituents at position 4 and 5 of the indole nucleus. The new IASs inhibited the HIV-1 replication in human T-lymphocyte (CEM) cells at low/subnanomolar concentration and were weakly cytostatic. Against the mutant L100I, K103N, and Y181C RT HIV-1 strains in CEM cells, sulfones 3, 4, 19, 27, and 31 were comparable to EFV. The new IASs were inhibitors to Coxsackie B4 virus at low micromolar (2-9 microM) concentrations. Superimposition of PLANTS docked conformations of IASs 19 and 9 revealed different hydrophobic interactions of the 3,5-dimethylphenyl group, for which a staking interaction with Tyr181 aromatic side chain was observed. The binding mode of 19 was not affected by the L100I mutation and was consistent with the interactions reported for the WT strain.

Indolylarylsulfones bearing natural and unnatural amino acids. Discovery of potent inhibitors of HIV-1 non-nucleoside wild type and resistant mutant strains reverse transcriptase and coxsackie B4 virus.

The opioid agonists endomorphins (Tyr-Pro-Trp-Phe-NH(2); EM1 and Tyr-Pro-Phe-Phe-NH(2); EM2) and morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) exhibit an extremely high selectivity for mu-opioid receptor. Here a series of novel EM2 and morphiceptin analogues containing in place of the proline at position 2 the S and R residues of beta-homologues of proline (HPro), of 2-pyrrolidinemethanesulphonic acid (HPrs) and of 3-pyrrolidinesulphonic acid (betaPrs) have been synthesized and their binding affinity and functional activity have been investigated. The highest micro-receptor affinity is shown by [(S)betaPrs(2)]EM2 analogue (6e) which represents the first example of a beta-sulphonamido analogue in the field of opioid peptides.

Synthesis and activity of endomorphin-2 and morphiceptin analogues with proline surrogates in position 2.

Detection of enzyme activity through catalytic signal amplification with functionalized gold nanoparticles.

We report the synthesis and fibrillogenesis inhibiting activity of the new peptide derivatives 1-4, related to the pentapeptide Ac-LPFFD-NH(2) (iAÎ²5p), proposed by Soto and co-workers and widely recognized as one of the most active Î²-sheet breaker agents. The AÎ²(25-35) fragment of the parent full-length AÎ²(1-42) was used as fibrillogenesis model. The activity of peptide derivatives 1-4 was tested in vitro by thioflavin T binding assay, far UV CD spectroscopy, and scanning electron microscopy. Their ability to hinder the toxic effect of AÎ²(25-35) in vivo was studied by monitoring the viability of human SH-SY5Y neuroblastoma cells and the prevention of superoxide anion radical release from BV2 microglial cells. The results point to a favourable role in the fibrillogenesis inhibitory activity of the sulphonamide junction for compounds 1 and 2, containing an N,N-dimethyltaurine and a taurine amino-terminal moiety, respectively. Furthermore, compounds 1 and 2 show a significant protective effect on cell viability, rescuing the cells from the toxicity exerted by AÎ²(25-35) treatment.

Inhibition of amyloid peptide fragment AÎ²25-35 fibrillogenesis and toxicity by N-terminal Î²-amino acid-containing esapeptides: is taurine moiety essential for in vivo effects?

The biological consequences of free radical production is the central subject of a very lively scientific debate, focusing on the estimation of the type and extent of damage, as well as the efficiency of the protective and repair systems. When studying free radical based chemical mechanisms, it is very important to establish biomimetic models, which allow the experiments to be performed in a simplified environment, but suitably designed to be in strict connection with cellular conditions. The biomimetic modeling approach has been coupled with physical organic chemistry methodologies and knowledge of free radical reactivity. Molecular basis of important processes have been identified, building up molecular libraries of products concerning unsaturated lipids, sulfur-containing proteins and nucleic acids, to be developed as biomarkers. Ongoing projects in our group deal with lipidomics, genomics and proteomics of free radical stress and some examples will be described.

Article	Year
Beta-peptido sulfonamides: for-Met-Leu-Phe-OMe analogues containing taurine and chiral beta-amino-ethanesulfonic acid residues. Farmaco (SocietÃ chimica italiana : 1989)\| PubMed ID: 15598430	2004
Alpha-peptide/beta-sulfonamidopeptide hybrids: analogs of the chemotactic agent for-Met-Leu-Phe-OMe. Bioorganic & medicinal chemistry\| PubMed ID: 16356729	2006
Effects of intra-articular administration of glucosamine and a peptidyl-glucosamine derivative in a rabbit model of experimental osteoarthritis: a pilot study. Rheumatology international\| PubMed ID: 17924112	2008
Synthesis and activity of fibrillogenesis peptide inhibitors related to the 17-21 beta-amyloid sequence. European journal of medicinal chemistry\| PubMed ID: 18501995	2009
Synthesis and bioactivity of chemotactic tetrapeptides: fMLF-OMe analogues incorporating spacer aminoacids at the lateral positions. Amino acids\| PubMed ID: 18636221	2009
Indolylarylsulfones bearing natural and unnatural amino acids. Discovery of potent inhibitors of HIV-1 non-nucleoside wild type and resistant mutant strains reverse transcriptase and coxsack... Journal of medicinal chemistry\| PubMed ID: 19281225	2009
Synthesis and activity of endomorphin-2 and morphiceptin analogues with proline surrogates in position 2. European journal of medicinal chemistry\| PubMed ID: 20692738	2010
Detection of enzyme activity through catalytic signal amplification with functionalized gold nanoparticles. Angewandte Chemie (International ed. in English)\| PubMed ID: 21351342	2011
Inhibition of amyloid peptide fragment AÎ²25-35 fibrillogenesis and toxicity by N-terminal Î²-amino acid-containing esapeptides: is taurine moiety essential for in vivo effects? Chemical biology & drug design\| PubMed ID: 21995332	2012
Biomimetic models of radical stress and related biomarkers. Chimia\| PubMed ID: 22871276	2012

Anna Sansone

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