Researchers have revealed that the inhibition of enterovirus A71 (EV-A71) replication can be achieved by targeting the human coatomer subunit zeta-1 (COPZ1) using a marine natural product derivative known as MPA-CF3. 

Enterovirus_71_(8405362662)

Source: AJC1

Enterovirus 71

COPZ1, a protein associated with iron metabolism and the viability of thyroid cancer cells, is crucial for the replication of enterovirus 71. This discovery was first reported in 2012 by Chinese virologist Qi Jin from the Chinese Academy of Medical Sciences and Peking Union Medical College.

This study is spearheaded by researcher Wu Zhong (National Engineering Research Center for the Emergence Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing) and Prof. Yong Qin (West China School of Pharmacy, Sichuan University).

Homing in on a target

In a recent effort to identify the anti-EV-A71 target of a marine natural product marinopyrrole A derivative (MPA-CF3), they employed a quantitative chemoproteomic approach and identified the specific target of MPA-CF3 as host factor COPZ1. “This marks the inaugural instance of us uncovering a small-molecule ligand with antiviral activity of COPZ1, despite COPZ1 serving multiple physiological roles,” researcher Zhong says.

They determined the binding affinity between MPA-CF3 and COPZ1 by surface plasmon resonance analysis, which revealed a strong interaction between the two partners. Through a range of phenotypic validation analysis, researchers demonstrated that COPZ1 knockdown by siRNA in human rhabdomyosarcoma (RD) cells resulted in a significant reduction in EV-A71 replication, as well as the expression of viral capsid protein VP1, confirming the target engagement of COPZ1 for EV-A71 replication.

The study showed that MPA-CF3 inhibits EV-A71 replication in a concentration-dependent manner and is eight-fold more potent than adenosine analogue NITD008. “Given the structurally significant disparity between MPA-CF3 and NITD008, MPA-CF3 may possess a unique antiviral mechanism of action,” says researcher Zhong.

Mechanism of action

To unravel the mechanism of action (MOA) of MPA-CF3 against EV-A71, Zhong’s team conducted protein thermal shift assay to determine the effect of MPA-CF3 on the stability of COPZ1. “MPA-CF3 destabilizes COPZ1 upon binding，and the subsequent disruption of the interaction of COPZ1 with EV-A71 2C protein, as confirmed by co-immunoprecipitation analysis, could signify its primary antiviral MOA,” explained first author Dr. Li.

Low-Res_图片1 (6)

Source: Researcher Wu Zhong, Prof. Yong Qin

MPA-CF3 specifically binds to COPZ1, a subunit of COPI. Upon binding, MPA-CF3 destabilizes COPZ1 and disrupts the interaction of COPZ1 with the EV-A71 2C protein in a concentration-dependent manner. The destruction of this interaction blocks the COPI coat-mediated transport of 2C to ER and ultimately inhibits EV-A71 replication.

The elucidation of the novel MOA regarding MPA-CF3 against EV-A71 will propel the advancement of host-targeting antivirals and provide an opportunity for effective combination therapies with other direct-acting antivirals for EV-A71 cure.

The financial support of this study were from the National Key Research and Development Project (No. 2021YFC2300704, China). Xiaoyong Li and Jin Zhang are co-first authors, West China School of Pharmacy, Sichuan University. College of Chemistry and Molecular Engineering, Peking University, respectively.

Topics