Fiorenza Falcioni

Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules

We have identified a heptapeptide with high affinity to rheumatoid arthritis–associated class II major histocompatibility (MHC) molecules. Using a model of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino acids and dipeptide mimetics were found to be appropriate substituents and could be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fold to more than a thousand-fold more potent than the original peptide in inhibiting T-cell responses to processed protein antigens presented by the target MHC molecules. Peptidomimetic compounds of this type could find therapeutic use as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases.

Identification of a novel class of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents with protein tyrosine phosphatase inhibitory activity.

A novel series of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents have been identified. These compounds show non-selective inhibitory properties against a panel of protein tyrosine phosphatases including PTP1B. Compounds 12 and 13 display oral glucose lowering effects in ob/ob mice.

Binding affinity independent contribution of peptide length to the stability of peptide-HLA-DR complexes in live antigen presenting cells

The effect of peptide length on the stability of peptide-HLR-DR1 (DR1) complexes was analyzed using two peptide series of increasing length, each containing a 7mer core with five DR1-binding anchors, extended stepwise with Ala residues at the N- and C-terminus, respectively. The Ala extensions, although did not affect binding affinity, significantly increased the half lives of peptide-DR1 complexes (from 1.5 h up to 10 h) in live antigen presenting cells (APC). Flanking residues from position -2 to 0 and 8 to 11 were involved in the affinity-independent increase of complex stability. The shortest (8mer and 9mer) peptides, with in vivo half lives of <2.5 h, were unable to form stable complexes with DR1 in presence of HLA-DM (DM) molecules, and were poor competitors of antigen presentation. Longer peptides were resistant to DM-mediated unloading, and were efficient competitors of antigen presentation. Thus, DM appears to limit short peptides in establishing biologically relevant DR occupancy, despite their high binding affinity. In APC, stable complexes can form only with high affinity peptides of >9 residues, and the longevity of complexes seems to depend on full of occupation of the binding site.

Potent, selective MCH-1 receptor antagonists.

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.

SAR of Melanin-concentration Hormone (MCH), an Important Regulatory Hormone in Feeding Behavior

Melanin-concentrating hormone is a cyclic hypothalamic neuropeptide [NH2-Asp-Phe-Asp-Met-Leu-Arg-Cys-Met-Leu-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Gln-Val-COOH cyclo Cys-Cys (7–16)] that was first characterized in chum salmon pituitary as a hormone responsible for color changes in response to environmental stimuli [1]. In mammals, MCH appears to have evolved into an important regulatory hormone in feeding behavior [2]. The MCH peptide is expressed in the hypothalamus, a region involved in energy balance and food intake. In the hypothalamus, MCH mRNA is overexpressed and upregulated during fasting in ob/ob mice and rats. Intra-cerebroventricular injections of MCH promote feeding in mice and rats. Transgenic mice (Tg) lacking the MCH gene are lean and hypophagic, while Tg mice overexpressing MCH in the hypothalamus are hyperphagic, obese, and insulin resistant. Consequently, a potent MCH antagonist is regarded as potentially useful in therapeutic approaches to obesity management. Efforts to identify the ligands for orphan GPCRs have recently led to the discovery of the receptor for MCH [3,4]. Receptor cloning and identification of functional assays for MCHR1 receptor allow the study of receptor/ligand interaction. One possible strategy consists of chemical modifications of the natural ligand (MCH) including: N- and C-termini truncations, Ala substitutions, D-amino acid replacements, and ring size variations, with the goal to identify the critical amino acid residues responsible for agonist or antagonist activity. Here, we describe a detailed SAR of MCH peptides on MCHR1.