First generation inhibitors of the adenovirus proteinase.

As there are more than 50 adenovirus serotypes, the likelihood of developing an effective vaccine is low. Here we describe inhibitors of the adenovirus proteinase (AVP) with the ultimate objective of developing anti-adenovirus agents. Inhibitors were identified via structure-based drug design using as druggable sites the active site and a conserved cofactor pocket in the crystal structures of AVP. A lead compound was identified that had an IC50 of 18 µM. One of eight structural derivatives of the lead compound had an IC50 of 140 nM against AVP and an IC50 of 490 nM against the AVP with its cofactor bound.