5 research outputs found
Multivalent Glycomimetics with Affinity and Selectivity toward Fucose-Binding Receptors from Emerging Pathogens
Bacterial
and fungal pathogens involved in lung infection in cystic
fibrosis patients utilize a particular family of glycan-binding proteins,
characterized by the presentation of six fucose-binding sites on a
ring-shaped scaffold. These lectins are attractive targets for anti-infectious
compounds that could interfere in the recognition of host tissues
by pathogens. The design of a cyclopeptide-based hexavalent structure
allowed for the presentation of six fucose residues. The synthetic
hexavalent compound displays liable geometry resulting in high-avidity
binding by lectins from <i>Aspergillus fumigatus</i> and <i>Burkholderia ambifaria</i>. Replacing the
fucose residue with a conformationally constrained fucomimetic does
not alter the affinity and provides fine specificity with no binding
to other fucose-specific lectins
Antigenic GM3 Lactone Mimetic Molecule Integrated Mannosylated Glycopeptide Nanofibers for the Activation and Maturation of Dendritic Cells
The ability of dendritic cells to
coordinate innate and adaptive
immune responses makes them essential targets for vaccination strategies.
Presentation of specific antigens by dendritic cells is required for
the activation of the immune system against many pathogens and tumors, and nanoscale materials can be functionalized for active targeting of dendritic cells. In this work, we integrated an immunogenic, carbohydrate melanoma-associated
antigen-mimetic GM3-lactone molecule into mannosylated peptide amphiphile
nanofibers to target dendritic cells through DC-SIGN receptor. Based
on morphological and functional analyses, when dendritic cells were
treated with peptide nanofiber carriers, they showed significant increase
in antigen internalization and a corresponding increase in the surface
expression of the activation and maturation markers CD86, CD83 and
HLA-DR, in addition to exhibiting a general morphology consistent
with dendritic cell maturation. These results indicate that mannosylated
peptide amphiphile nanofiber carriers are promising candidates to
target dendritic cells for antigen delivery
GM‑3 Lactone Mimetic Interacts with CD4 and HIV‑1 Env Proteins, Hampering HIV‑1 Infection without Inducing a Histopathological Alteration
Glycosphingolipids (GSLs) are involved
in HIV-1 entry. GM-3 ganglioside, a widespread GSL, affects HIV entry
and infection in different ways, depending on the concentration, through
its anchoring activity in lipid rafts. This explains why the induction
of an altered GSLs metabolism was a tempting approach to reducing
HIV-1 cell infection. This study assayed the biological properties
of a synthetic GM-3 lactone mimetic, <b>1</b>, aimed at blocking
HIV-1 infection without inducing the adverse events expected by an
altered metabolism of GLSs in vivo. The mimetic, conjugated to immunogenic
protein ovalbumin and multivalently presented, was able to bind the
CD4 molecule with high affinity and block its engagement with gp120,
thus inhibiting virus entry. Elicited antimimetic antibodies were
also able to block HIV-1 infection in vitro, with activity complementary
to that observed for <b>1</b>. These preliminary results show
that the use of GSLs mimetics can be a novel promising mode to block
HIV-1 infection and that <b>1</b> and other GSL mimetics deserve
further attention
Lipoic-Based TRPA1/TRPV1 Antagonist to Treat Orofacial Pain
Inflammation of the
trigeminal nerve is considered one of the most
painful conditions known to humankind. The diagnosis is often difficult;
moreover, safe and effective pharmacological treatments are lacking.
A new molecule, ADM_12, formed by a lipoic and omotaurine residues
covalently linked, is here reported. In vitro and in vivo tests showed
that ADM_12 is a very attractive original compound presenting (i)
a remarkable safety profile; (ii) a high binding constant versus TRPA1;
(iii) an intriguing behavior versus TRPV1; and (iv) the ability to
significantly and persistently reduce mechanical facial allodynia
in rats. Noteworthy, by testing ADM_12, we shed light on the unprecedented
involvement of TRPA1 and TRPV1 channels in orofacial pain
Lipoyl-Homotaurine Derivative (ADM_12) Reverts Oxaliplatin-Induced Neuropathy and Reduces Cancer Cells Malignancy by Inhibiting Carbonic Anhydrase IX (CAIX)
Oxaliplatin (OXA) is a valuable and
largely used cancer drug which
induces a serious and intractable neuropathy. The lipoyl-homotaurine
derivative (<b>ADM_12</b>) reverts in vivo OXA-induced neuropathy,
and it is an effective antagonist of the nociceptive sensor channel
TRPA1. Unprecedentedly, this safe analgesic showed a synergy with
OXA in vitro and proved to inhibit CA IX, a relevant therapeutic target,
clearly interfering with pancreatic cancer cells’ aggressiveness