Reena Zutshi

Selective amplification by auto- and cross-catalysis in a replicating peptide system

Self-replication has been demonstrated in synthetic chemical systems based on oligonucleotides, peptides and complementary molecules without natural analogues. However, within a living cell virtually no molecule catalyses its own formation, and the search for chemical systems in which both auto- and cross-catalysis can occur has therefore attracted wide interest. One such system, consisting of two self-replicating peptides that catalyse each others production, has been reported. Here we describe a four-component peptide system that is capable of auto- and cross-catalysis and allows for the selective amplification of one or more of the products by changing the reaction conditions. The ability of this system selectively to amplify one or more molecules in response to changes in environmental conditions such as pH or salt concentration supports the suggestion that self-replicating peptides may have played a role in the origin of life.

Inhibiting the assembly of protein-protein interfaces.

Protein-protein association is found throughout mechanisms of cellular growth and differentiation, and viral replication. Inhibiting the assembly of protein complexes, therefore, presents itself as a novel means of inhibition for a wide variety of cellular and viral events. Peptides and small molecules that modify the overall quaternary structure of a selection of receptor-ligand interactions and oligomeric viral enzymes have been developed recently.

A self-replicating peptide under ionic control

The chemical coupling of two peptide fragments to give the peptide K1 K2 (shown in the helical wheel diagram on the right) is autocatalytic at high NaClO4 concentrations (1 M). Under these conditions K1 K2 assumes a coiled-coil conformation, which can function as a template for the coupling. Autocatalysis is not observed under conditions that prevent formation of the coiled-coil conformation.

Targeting the dimerization interface for irreversible inhibition of HIV-1 protease

A novel strategy was used to irreversibly inhibit HIV-1 protease. The inhibitor was designed to form a disulfide bond with Cys95, present at the dimerization interface of HIV-1 protease. The inhibitor was shown to be active against HIV-1 protease with K(inact) = 3.7 microM and V(inact) = 0.012 min(-1).