Structural Insights into the Mechanisms of Action of Functionally Distinct Classes of Chikungunya Virus Nonstructural Protein 1 Inhibitors
Kristína Kováčiková, Marina Gorostiola González, Rhian Jones, Juan Reguera, Alba Gigante, María‐Jesús Pérez‐Pérez, Gerhard Pürstinger, Julia Moesslacher, Thierry Langer, Lak Shin Jeong, Leen Delang, Johan Neyts, Eric J. Snijder, Gerard J. P. van Westen, Martijn J. van Hemert
Abstract
ligomerization (RAMBO) domain, potentially interfering with the membrane binding and oligomerization of nsP1. Our cell-based and enzymatic assays, in combination with molecular docking and mapping of compound resistance mutations to the nsP1 structure, allowed us to group nsP1 inhibitors into functionally distinct classes. This study identified druggable pockets in the nsP1 dodecameric structure and provides a basis for the rational design, optimization, and combination of inhibitors of this unique and promising antiviral drug target.