First phosphonic-type inhibitors and activity-based probes specific to the O'nyong-nyong virus capsid protease.

The O'nyong-nyong virus (ONNV) is a member of the Alphavirus genus isolated for the first time in 1959 in Gulu (Uganda). The main symptoms of O'nyong-nyong fever are nonspecific and flu-like; a proper diagnosis at the early stage is challenging. Until today, the first ONNV epidemic in 1959-1962 remains one of the largest arbovirus outbreaks ever recorded (over 2 million cases). No specific therapy is available thus far. Capsid protease (CP) is a chymotrypsin-like serine protease that catalyzes the autoproteolytic maturation of the structural polyprotein and undergoes self-inactivation upon the release of the mature capsid (C) protein. Despite the discovery of this virus more than 60 years ago, many aspects of CP remain understudied, including substrate specificity. Here we present the structures of the first phosphonic-type inhibitors and activity-based probes specific to the ONNV CP.