Synthesis of 10,10′-bis(trifluoromethyl) marinopyrrole A derivatives and evaluation of their antiviral activities in vitro

Xiao, Yaxin; Yang, Jingjing; Zou, Liangjing; Wu, Pingzhou; Li, Wei; Yan, Yunzheng; Li, Yuexiang; Li, Song; Song, Hao; Zhong, Wu; Qin, Yong

doi:10.1016/j.ejmech.2022.114436

Cited by 5 publications

(8 citation statements)

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“…50 Compounds 2, 3, and 4 were prepared based on a previous study. 51 Side chain (compound 4) was reacted with MPA-CF 3 to yield the photoaffinity probe MPA-P. 11 The detailed preparation of each compound is listed in Method S1, Supporting Information.…”

Section: Synthesis Of the Photoaffinity Probe Mpa-pmentioning

confidence: 99%

“…We previously reported 10,10′‐bis(trifluoromethyl) marinopyrrole A derivative (termed MPA‐CF 3 ) with excellent antiviral activity against EV‐A71 and coxsackievirus A16 through phenotypic screening. 11 In this study, we constructed and synthesized a clickable photoaffinity probe of MPA‐CF 3 to globally explore the antiviral targets in EV‐A71‐infected human rhabdomyosarcoma (RD) cells. Chemoproteomics disclosed that the primary target of MPA‐CF 3 is the host factor coatomer subunit zeta‐1 (COPZ1), which was further validated by biophysical and biochemical assays.…”

Section: Introductionmentioning

confidence: 99%

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Chemoproteomics enables identification of coatomer subunit zeta‐1 targeted by a small molecule for enterovirus A71 inhibition

Li,

Zhang,

Xiao

et al. 2024

MedComm

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Human enterovirus A71 (EV‐A71) is a significant etiological agent responsible for epidemics of hand, foot, and mouth disease (HFMD) in Asia‐Pacific regions. There are presently no licensed antivirals against EV‐A71, and the druggable target for EV‐A71 remains very limited. The phenotypic hit 10,10′‐bis(trifluoromethyl) marinopyrrole A derivative, herein termed MPA‐CF3, is a novel potent small‐molecule inhibitor against EV‐A71, but its pharmacological target(s) and antiviral mechanisms are not defined. Here, quantitative chemoproteomics deciphered the antiviral target of MAP‐CF3 as host factor coatomer subunit zeta‐1 (COPZ1). Mechanistically, MPA‐CF3 disrupts the interaction of COPZ1 with the EV‐A71 nonstructural protein 2C by destabilizing COPZ1 upon binding. The destruction of this interaction blocks the coatomer‐mediated transport of 2C to endoplasmic reticulum, and ultimately inhibits EV‐A71 replication. Taken together, our study disclosed that MPA‐CF3 can be a structurally novel host‐targeting anti‐EV‐A71 agent, providing a structural basis for developing the COPZ1‐targeting broad‐spectrum antivirals against enteroviruses. The mechanistic elucidation of MPA‐CF3 against EV‐A71 may offer an alternative COPZ1‐involved therapeutic pathway for enterovirus infection.

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Section: Synthesis Of the Photoaffinity Probe Mpa-pmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemoproteomics enables identification of coatomer subunit zeta‐1 targeted by a small molecule for enterovirus A71 inhibition

Li,

Zhang,

Xiao

et al. 2024

MedComm

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“…[1,2,4]pyrimidin-5 (4H)-ones like AD compound have been evaluated for antiviral ability against human enteroviruses such as (Cox B3), (Cox B1), Poliovirus 3, and Human Rhinovirus 14, 21, and 71 (77). Compound AD is a promising lead compound for developing broad spectrum antienterovirus drugs (78).…”

Section: Figure (19)mentioning

confidence: 99%

Synthesis and Biological Activities of Some 1,2,4-Triazole Derivatives: A Review

Ameen¹,

Hamdi²,

Khan³

2022

AJPS

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“…12 However, the conclusion that 1 is a selective Mcl-1 inhibitor has been called into question. 13,14 Various reports detailing the deleterious biological effects of 1−3 in mammalian cells, 15 plants, 16 phytoplankton, 17 viruses, 18 and parasitic protozoans 19−21 continue to be disclosed. Although the original reports of these unusual compounds were tied to their antibacterial activity, where they uniformly showed potent activity against Gram-positive pathogens and little or no activity against Gramnegative pathogens, 22,23 little work regarding their antibacterial mechanism of action has been reported.…”

mentioning

confidence: 99%

“…Since the compounds have pronounced cytotoxicity against cancer cell lines, various studies have focused on the antieukaryotic properties of 1– 3 , wherein actin, Mcl-1, and others have been identified as eukaryotic targets for MarA ( 1 ), myosin for PBP ( 2 ) and PCP ( 3 ), − and human lipoxygenases 15-hLO and 12-hLO for 2 . However, the conclusion that 1 is a selective Mcl-1 inhibitor has been called into question. , Various reports detailing the deleterious biological effects of 1 – 3 in mammalian cells, plants, phytoplankton, viruses, and parasitic protozoans − continue to be disclosed. Although the original reports of these unusual compounds were tied to their antibacterial activity, where they uniformly showed potent activity against Gram-positive pathogens and little or no activity against Gram-negative pathogens, , little work regarding their antibacterial mechanism of action has been reported.…”

mentioning

confidence: 99%

Antibacterial Marinopyrroles and Pseudilins Act as Protonophores

Castro-Falcón,

Straetener,

Bornikoel

et al. 2024

ACS Chem. Biol.

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Elucidating the mechanism of action (MoA) of antibacterial natural products is crucial to evaluating their potential as novel antibiotics. Marinopyrroles, pentachloropseudilin, and pentabromopseudilin are densely halogenated, hybrid pyrrole-phenol natural products with potent activity against Gram-positive bacterial pathogens like Staphylococcus aureus. However, the exact way they exert this antibacterial activity has not been established. In this study, we explore their structure−activity relationship, determine their spatial location in bacterial cells, and investigate their MoA. We show that the natural products share a common MoA based on membrane depolarization and dissipation of the proton motive force (PMF) that is essential for cell viability. The compounds show potent protonophore activity but do not appear to destroy the integrity of the cytoplasmic membrane via the formation of larger pores or interfere with the stability of the peptidoglycan sacculus. Thus, our current model for the antibacterial MoA of marinopyrrole, pentachloropseudilin, and pentabromopseudilin stipulates that the acidic compounds insert into the membrane and transport protons inside the cell. This MoA may explain many of the deleterious biological effects in mammalian cells, plants, phytoplankton, viruses, and protozoans that have been reported for these compounds.

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Synthesis of 10,10′-bis(trifluoromethyl) marinopyrrole A derivatives and evaluation of their antiviral activities in vitro

Cited by 5 publications

References 50 publications

Chemoproteomics enables identification of coatomer subunit zeta‐1 targeted by a small molecule for enterovirus A71 inhibition

Chemoproteomics enables identification of coatomer subunit zeta‐1 targeted by a small molecule for enterovirus A71 inhibition

Synthesis and Biological Activities of Some 1,2,4-Triazole Derivatives: A Review

Antibacterial Marinopyrroles and Pseudilins Act as Protonophores

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