Cinzia Esposito

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.

Conformational Stability of Aβ-(25–35) in the Presence of Thiazolidine Derivatives

In the attempt to identify a new lead compound able to modify the conformational preferences of the β‐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 β‐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.

Antibodies Generated in Cats by a Lipopeptide Reproducing the Membrane-Proximal External Region of the Feline Immunodeficiency Virus Transmembrane Enhance Virus Infectivity

ABSTRACT 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 to be positioned at the membrane interface, displayed a large number of ordered structures folded in turn helices, and was as active as lipo-P59 alone at inhibiting FIV infectivity in vitro. The antibodies developed differed from the ones previously obtained by immunizing cats with the nonlipoylated version of the peptide (G. Freer, S. Giannecchini, A. Tissot, M. F. Bachmann, P. Rovero, P. F. Serres, and M. Bendinelli, Virology 322:360-369, 2004) in epitope specificity and in the fact that they bound FIV virions. However, they too lacked virus-neutralizing activity and actually enhanced FIV infectivity for lymphoid cell cultures. It is concluded that the use of MPER-reproducing oligopeptides is not a viable approach for vaccinating against FIV.