AND PSEUDOPEPTIDE INHIBITORS OF HIV ASPARTIC PROTEASE

The laboratory is involved in the characterization of mammalian antimicrobial peptides, and the de novo design of artificial antimicrobial peptides.  Mammalian peptides are studied  in regards to the evolutionary mechanisms that may have determined their structures and properties, in primates in particular.

Evolutionary variations are correlated with structural properties, probed by CD or FTIR in model systems, and to functional properties with respect to biological or model membranes or to microbial or host cells.

The design of novel peptides is based on the analysis and comparison of natural sequences, as present in the AMSDb antimicrobial sequences database, and extraction of significant sequence patterns. The resulting “sequence templates” are used to design novel sequences in which the physico-chemical properties (hydrophobicity, amphipaticity, charge, degree of structuring, etc.) are varied in a rational and controlled manner, also using appropriate non-proteinogenic amino acids, so as to obtain insights into structure/activity relationships.  The antimicrobial properties of the synthetic peptides are tested in laboratory strains of bacteria and fungi as well as on clinical isolates, while their cytotoxic properties are studied via flow cytometric analyses on circulating blood cells.

A second topic concerns the design, synthesis and evaluation of pseudopeptides with inhibitory activity on HIV-1 aspartic protease (PR), using a modular design and synthesis approach. Optimization of these compounds with respect to their mode of binding to the PR active site and to bioavailability may result in lead compounds for the development of anti-AIDS drugs.

This laboratory was part of the European "PANAD" (Peptides As Novel Antiinfective Drugs) consortium (European 5^th framework programme, project N° QLK2-CT-2000-00411).