Società Italiana di Fisica
Pubblicazioni
The physics of protein folding and of non-conventional drug design: attacking AIDS with its own weapons
Rivista del Nuovo Cimento Vol. 29, N. 3-4 (2006).
R.A. Broglia, G. Tiana, L. Sutto, D. Provasi and F. Simona
Life is exact reproduction and metabolic activity. The molecules of DNA are resp onsible for the first function, proteins for the second. To become biologically active, for example form the active site needed for enzym atic action, proteins, which are produced as linear chains by the ribosomes, fol d into unique three--dimensional structures (native conformation). To avoid aggr egation or denaturation folding has to take place in very short times. Theoretic al studies indicate that to do so proteins form, early in the folding process, f ew Local Elementary Structures (LES) as the result of the interaction between hy drophobic, strongly interacting, highly conserved (hot) amino acids. The docking of the LES gives rise to the post critical folding nucleus (FN). This event tri ggers the formation of the remaining native contacts shortly after. A consequence of these results is the fact that short peptides called p--LES, displaying the same amino acid sequence as that associated with the segments of the protein co rresponding to LES, are highly specific and effective inhibitors of the folding.
Furthermore, these non--conventional inhibitors unlikely will induce resistance in the organism expressing the protein as they attach to the protein through ho t amino acids. They are thus particular suited to fight viruses and bacteria dis playing a high degree of variability (mutations). 
The p--LES strategy has been used in the design of a non--conventional inhibitor of the HIV--1--Protease, an enzyme which plays an essential role in the life cy cle of the Immuno Deficiency Virus (HIV). Experimental data on infected cells te stify to the fact that this non--conventional inhibitor prevents the maturation of the virus, also in the case in which the cells are infected with a variant of the virus resistant to all conventional drugs (molecules which cup the active s ite) available in the market. This promising lead for developing a drug against the virus which can cause AIDS is now entering the preclinical test stage and will eventually undergo those co rresponding to the clinical phases sometimes next year. In the present paper the physics which is at the basis of the design of a non--conventional HIV--1--Protease inhibitor is reviewed. It can be used as paradigm f or designing folding inhibitors of other target proteins associated with the sam e or other pathogenic viruses or bacteria.
