Challenges for developing selective viral protease inhibitors as antiinfectives.

The biochemical machinery of most viruses comprises proteases which are crucial for their life cycle. In the last decades, proteases from pathogenic viruses started to be considered as potential drug targets, and this led to the development of several classes of effective antivirals used for the management of HIV, HCV and SARS CoV 2 infections. More than 25 clinically used protease inhibitors (PIs) are now available for the management of these three infections, but many other viruses encode for proteases which started to be considered only recently as potential drug targets. They include enterovirises, filoviruses such as Zika, Dengue and West Nile viruses, Chikungunya and other togaviruses, Ebola, Marbug and many other hemorrhagic viruses. The proteases of many such pathogens have been cloned, characterized and in some cases also crystallized in complex with inhibitors, but no compounds progressed yet to clinical trials. There are several relevant challenges in designing PIs as novel antivirals, such as: (i) the drug design strategies of peptidomimetic inhibitors, which are many times complex and expensive; (ii) the difficulties in identifying non-peptidomimetic PIs; (iii) the selectivity for the target versus host proteases of the identified PIs; (iv) their metabolism, absorption and in vivo antiviral activity, and, most importantly, (v) the emergence of drug/multidrug resistance due to the high mutation rates of many viruses. Many of these challenges started to be approached by innovative strategies which will be duscussed in the chapter.