title: Computer-aided identification, design and synthesis of a novel series of compounds with selective antiviral activity against chikungunya virus.
abstract: Chikungunya virus (CHIKV) is an Arbovirus that is transmitted to humans primarily by the mosquito species Aedes aegypti. Infection with this pathogen is often associated with fever, rash and arthralgia. Neither a vaccine nor an antiviral drug is available for the prevention or treatment of this disease. Albeit considered a tropical pathogen, adaptation of the virus to the mosquito species Aedes albopictus, which is also very common in temperate zones, has resulted in recent outbreaks in Europe and the US. In the present study, we report on the discovery of a novel series of compounds that inhibit CHIKV replication in the low μM range. In particular, we initially performed a virtual screening simulation of ∼5 million compounds on the CHIKV nsP2, the viral protease, after which we investigated and explored the Structure-Activity Relationships of the hit identified in silico. Overall, a series of 26 compounds, including the original hit, was evaluated in a virus-cell-based CPE reduction assay. The study of such selective inhibitors will contribute to a better understanding of the CHIKV replication cycle and may represents a first step towards the development of a clinical candidate drug for the treatment of this disease.
authors: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors: Marcella
authors: M
authors: Bassetto
authors: Tine
authors: T
authors: De Burghgraeve
authors: Leen
authors: L
authors: Delang
authors: Alberto
authors: A
authors: Massarotti
authors: Antonio
authors: A
authors: Coluccia
authors: Nicola
authors: N
authors: Zonta
authors: Valerio
authors: V
authors: Gatti
authors: Giampiero
authors: G
authors: Colombano
authors: Giovanni
authors: G
authors: Sorba
authors: Romano
authors: R
authors: Silvestri
authors: Gian Cesare
authors: GC
authors: Tron
authors: Johan
authors: J
authors: Neyts
authors: Pieter
authors: P
authors: Leyssen
authors: Andrea
authors: A
authors: Brancale
mesh_terms: D018354:Alphavirus Infections / Q000188:drug therapy / Q000821:virology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000187:drug effects* / Q000502:physiology; D017076:Computer-Aided Design; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents