  One of the main problems of drug design is that of optimizing the
drug--target interaction. In the case in which the target is a viral protein
displaying a high mutation rate, a second problem arises, namely the eventual
development of resistance. We wish to suggest a scheme for the design of
non--conventional drugs which do not face any of these problems and apply it to
the case of HIV--1 protease. It is based on the knowledge that the folding of
single--domain proteins, like e.g. each of the monomers forming the HIV--1--PR
homodimer, is controlled by local elementary structures (LES), stabilized by
local contacts among hydrophobic, strongly interacting and highly conserved
amino acids which play a central role in the folding process. Because LES have
evolved over myriads of generations to recognize and strongly interact with
each other so as to make the protein fold fast as well as to avoid aggregation
with other proteins, highly specific (and thus little toxic) as well as
effective folding--inhibitor drugs suggest themselves: short peptides (or
eventually their mimetic molecules), displaying the same amino acid sequence of
that of LES (p--LES). Aside from being specific and efficient, these inhibitors
are expected not to induce resistance: in fact, mutations which successfully
avoid their action imply the destabilization of one or more LES and thus should
lead to protein denaturation. Making use of Monte Carlo simulations within the
framework of a simple although not oversimplified model, which is able to
reproduce the main thermodynamic as well as dynamic properties of monoglobular
proteins, we first identify the LES of the HIV--1--PR and then show that the
corresponding p--LES peptides act as effective inhibitors of the folding of the
protease which do not create resistance.

Biomolecules