Learning to design resistance proof drugs from folding

Learning how proteins fold will hardly have any impact on the way conventional — active site centered — drugs are designed. On the other hand, this knowledge is proving instrumental in defining a new paradigm for the identification of drugs against any target protein: folding inhibition. Targeting folding renders drugs less susceptible to spontaneous genetic mutations that in many cases, notably in connection with retroviruses like the Human Immunodeficiency Virus (HIV), can abrogate drug effect. The progress which has taken place during the last years to understand which are the sequences of amino acids which code for a protein, and how to read from these sequences the associated three-dimensional, biologically active, native structure, constitutes the main subject of the present paper. From this narrative the idea of folding inhibitors emerges both naturally and, to some extent, inescapably.