Recent advances of enterovirus 71 $$3{\rm C}^{{\rm pro}}$$ targeting Inhibitors

Abstract

With CA16, enterovirus-71 is the causative agent of hand foot and mouth disease (HFMD) which occurs mostly in children under 5 years-old and responsible of several outbreaks since a decade. Most of the time, HFMD is a mild disease but can progress to severe complications such as meningitis, brain stem encephalitis, acute flaccid paralysis (AFP) and even death; EV71 has been identified in all severe cases. Therefore, it is actually one of the most public health issues that threatens children’s life. $$3{\rm C}^{{\rm pro}}$$ 3 C pro is a protease which plays important functions in EV71 infection. To date, a lot of $$3{\rm C}^{{\rm pro}}$$ 3 C pro inhibitors have been tested but none of them has been approved yet. Therefore, a drug screening is still an utmost importance in order to treat and/or prevent EV71 infections. This work highlights the EV71 life cycle, $$3{\rm C}^{{\rm pro}}$$ 3 C pro functions and $$3{\rm C}^{{\rm pro}}$$ 3 C pro inhibitors recently screened. It permits to well understand all mechanisms about $$3{\rm C}^{{\rm pro}}$$ 3 C pro and consequently allow further development of drugs targeting $$3{\rm C}^{{\rm pro}}$$ 3 C pro . Thus, this review is helpful for screening of more new $$3{\rm C}^{{\rm pro}}$$ 3 C pro inhibitors or for designing analogues of well known $$3{\rm C}^{{\rm pro}}$$ 3 C pro inhibitors in order to improve its antiviral activity.

Children with severe enterovirus 71 infection

“…Considering that the lesions involved the dorsal nucleus of the vagus nerve and the nucleus of the solitary tract, or the inner acceleration center or vasoconstriction center of the reticular structure [26,27], it is possible that the lesions are caused by sympathetic excitation.…”

Seroprevalence of coxsackievirus A6 and enterovirus A71 infection in humans: a systematic review and meta-analysis

“…EV-A71 virus particles are icosahedral with a diameter of 24-30 nm and contain a single plus-stranded RNA [ 7 ]. Since the virus was first reported in the 1970s, epidemics of EV-A71 have been reported in many countries and regions [ 8 , 9 ].…”

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection

“…To prevent a pandemic, China has successfully developed an inactivated monovalent EV71 vaccine (Lin et al, 2019). However, there is still a lack of safe and reliable treatment for patients infected with EV71 (Diarimalala et al, 2020), and the risk of being permanently disabled or fatal after EV71 infection remains, there is a pressing need to develop anti-EV71 drugs to combat HFMD.…”

“…Structure-based drug design and screening based on 3C pro have identified several active compounds with significant inhibitory effects against EV71 infection (Supplementary Figure S1) (Diarimalala et al, 2020). In 2011, Rupintrivir (AG7088), a 3C pro inhibitor of human rhinovirus, was shown to have strong antiviral activity against EV71 3C pro (Wang et al, 2011).…”

“…In addition, several natural products and derivatives have been shown to have low cytotoxicity and potent antiviral activity, including Luteoloside (Cao et al, 2016), Quercetin (Yao et al, 2018), Chrysin and Diisopropyl Chrysin-7-i1 Phosphate (CPI) (Wang et al, 2014). However, the above active small molecules cannot reach the clinical stage due to their poor oral availability or higher toxicity and easy degradation, thus the discovery of antiviral agents that can enter clinical use is the most urgent task for EV71 drug development (Lu et al, 2011;Diarimalala et al, 2020).…”