WXP-003

Serine palmitoyltransferase (SPT) plays the key role on catalysing the formation of 3-ketodihydrosphingosine, which is the first step of the de novo biosynthesis of sphingolipids. SPT is linked to many diseases including fungal infection, making it a potential therapeutic target. Thus, a logical docking-based virtual screening method was used to screen selective SPT inhibitor against fungi, not human. We used myriocin-similarity database to identify compounds with good binding with fungal SPT and poor binding with homology human SPT model. Preliminary bio-assay led to the discovery of a promising inhibitor WXP-003, which displayed good inhibitory activity against diversity fungi strains with MIC ranging from 0.78 to 12.5 μg/mL. WXP-003 could significantly reduce sphingolipids content in fungi and no effect on mouse fibroblast cell line L929. Molecular dynamics simulation depicted that SPT/WXP-003 complex formed the favoured interactions. Taken together, discovery of WXP-003 provided valuable guide for the development of novel anti-fungal agents.

Surfactants are versatile excipients, which are commonly employed in several pharmaceutical formulations as emulsifiers, stabilizing or solubilizing agents.In this field, current research is aimed at the design or discovery of amphiphilic mols. with improved characteristics in terms of safety (toxicol. profile) and biol. activities (e.g. antimicrobial activity, interaction with biomembranes).Quaternary ammonium surfactants derived from amino acids are one such class of compounds with significant potential for pharmaceuticals.In this work, quaternary ammonium surfactants derived from the amino acids leucine and methionine and esterified with fatty acids of different lengths (C10, C12 and C14) were synthesized.These amphiphiles were characterized in terms of critical micelle concentration (CMC) by tensiometry and conductivity measurements, cytotoxicity (MTS and LDH assay on Caco-2 and Calu-3 cell lines) and antimicrobial activity on selected Gram-pos. (S. aureus and E. faecalis), Gram-neg. (E. coli and P. aeruginosa) and the fungus C. albicans.The derivatives bearing a C12 or a C14 chain displayed CMC, EC50 (from cytotoxicity assays) and min. inhibition concentration (MIC) values that are comparable to those of benzalkonium chloride (used as reference), especially towards Gram-pos. and C. albicans.On the contrary, derivatives bearing a C10 chain have higher CMC, EC50 and MIC values, highlighting the crucial role of the hydrophobic tail in determining both physicochem. and biol. properties.The C12-C14 synthesized derivatives may represent a promising alternative to benzalkonium chloride as surface active mols. and antimicrobial agents.