Antiviral activity of [1,2,3]triazolo[4,5- d ]pyrimidin-7(6 H )-ones against chikungunya virus targeting the viral capping nsP1

Abstract

Chikungunya virus (CHIKV) is a re-emerging alphavirus transmitted to humans by Aedes mosquitoes. Since 2005, CHIKV has been spreading worldwide resulting in epidemics in Africa, the Indian Ocean islands, Asia and more recently in the Americas. CHIKV is thus considered as a global health concern. There is no specific vaccine or drug available for the treatment of this incapacitating viral infection. We previously identified 3-aryl-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones as selective inhibitors of CHIKV replication and proposed the viral capping enzyme nsP1 as a target. This work describes the synthesis of novel series of related compounds carrying at the aryl moiety a methylketone and related oximes combined with an ethyl or an ethyl-mimic at 5-position of the triazolopyrimidinone. These compounds have shown antiviral activity against different CHIKV isolates in the very low μM range based on both virus yield reduction and virus-induced cell-killing inhibition assays. Moreover, these antivirals inhibit the in vitro guanylylation of alphavirus nsP1, as determined by Western blot using an anti-cap antibody. Thus, the data obtained seem to indicate that the anti-CHIKV activity might be related to the inhibition of this crucial step in the viral RNA capping machinery.

Small Molecule Inhibitors Targeting Chikungunya Virus

“…The most fully characterized inhibitors of CHIKV nsP1 target the GTase function of the capping machinery. MADTP-314 and MADTP-372 are CHIKV and VEEV nsP1 inhibitors that are part of the [1,2,3]trizolo[4,5-d]pyrimidin-7(6 h)ones (MADTP) compound series identified using a cell-based CHIKV replication screen (Gigante et al 2014(Gigante et al , 2017. CHIKV resistance to MADTP-314 occurs through a P34S mutation in nsP1 GTase functional domain that was validated by reverse genetics.…”

2019 meeting of the global virus network

“…Once a hit with antiviral properties has been identified, its optimization to become a lead is a multiparameter process, that can also be determined by the mechanism of action of the compound. Dr. Pérez Pérez' group's own experience in triazolopyrimidines as inhibitors of CHIKV replication was presented to illustrate how proactive and collaborative efforts among academic groups can lead to the identification and optimization of antivirals exploring a new mechanism of action (Gigante et al, 2014;Delang et al, 2016;Gigante et al, 2017;Gomez SanJuan et al, 2018).…”

Chikungunya Virus Infection: Why Should U.S. Geriatricians Be Aware of It?

“…General Overview of Therapeutic Approach to CHIKV Infection Although promising antivirals, 35,36 immunotherapy, 37,38 and vaccines 39,40 are being developed, there is no effective prevention or curative treatment for CHIKV. 41 Current therapeutic recommendations commonly consist of supportive care, 2 with plenty of rest, ensuring adequate fluid intake, and use of acetaminophen or NSAIDs to reduce pain and fever at the acute stage.…”