key: cord-0902410-4f4mabye authors: Zhang, Dong; Ma, Zhi; Chen, Hanchi; Lu, Yuele; Chen, Xiaolong title: Valinomycin as a potential antiviral agent against coronaviruses: a review date: 2020-08-11 journal: Biomed J DOI: 10.1016/j.bj.2020.08.006 sha: 4f3752b6c7c3ea11341f8fea6d281502fc9ca5fe doc_id: 902410 cord_uid: 4f4mabye Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been resulting in global epidemics with heavy morbidity and mortality. Unfortunately, there are currently no specific medicines that can better treat these coronaviruses. Drug repurposing is an effective and economical strategy for drug discovery from existing drugs, natural products, and synthetic compounds. In this review, the broad-spectrum antiviral activity of valinomycin (VAL), especially its activity against coronaviruses such as SARS-CoV, MERS-CoV, human coronavirus OC43 (HCoV-OC43), were summarized, it highlights that VAL has tremendous potential for use as a novel antiviral agent against SARS-CoV-2. isolated from a seven-month-old child with severe lower respiratory tract in Amsterdam in 142 2004 [17, 18] . Same as SARS-CoV and SARS-CoV-2, HCoV-NL63 enters its host cell by 143 binding to the ACE2 receptor [19] . HCoV-NL63 can cause mild upper respiratory illness with 144 symptoms of cough, fever, or rhinorrhea, or result in more serious lower respiratory tract 145 infections with symptoms of bronchiolitis and croup [74, 75] . Along with HCoV-OC43, 146 HCoV-NL63 are common causes of upper respiratory tract infections, which occur more 147 frequently than HCoV-HKU1 and HCoV-229E infections in early childhood [76] [77] [78] . VAL 148 showed inhibitory activity against HCoV-NL63 with an EC 50 value of 1.68 µM and a CC 50 149 value of 4.12 µM [70] . The mechanism of action of VAL against HCoV-NL63 has not been 150 investigated. 151 HCoV-229E is the first identified human coronavirus that belongs to a member of the valinomycin. The reduction in VSV titer in the presence of VAL may be due to a reduction in 171 the production of virus particles, in comparison with the releasing of noninfectious particles. 172 VAL affected the processing of glycoprotein (G protein). In the presence of VAL, G protein 173 oligosaccharides were sensitive to endo-b-N-acetylglucosaminidase H, which can cleave 174 high-mannose oligosaccharides but not complete processing of complex oligosaccharides. As 175 a result, most of the oligosaccharides in G protein were not converted into VSV G protein 176 with mature structure and function required for transport of G protein to the cell surface and 177 its further incorporation into budding particles. The addition of 10 µM valinomycin to the 178 infected Vero cells within the first three hours, resulted in a 90% reduction in viral titer 12 179 hours after infection. Of course, higher concentrations of valinomycin resulted in an even 180 greater reduction in viral titer. The activity of VAL against HBV was evaluated through exploring effects of Ca 2+ on the 205 nuclear localization of HBV Pol and p11 in HepG2 cells, which were incubated within 30 µM 206 VAL for 24 hours. The results showed that VAL promoted Ca 2+ influx, resulted in an 207 inhibition of the association of HBV Pol-p11 with the promyelocytic leukemia protein PML. 208 In other words, VAL showed anti-HBV activity in viral replication and transcription [83] . glycosides were identified as inhibitors of the membrane-bound Na + /K + -ATPase against the 244 replication of RSV. Notably, VAL has a high selectivity for intracellular K + relative to Na + 245 Therefore, the VAL was screened out as an anti-RSV inhibitor in human epithelial type 2 249 cells and primary nasal epithelial cells RSV with an IC 50 value of 0.0015 µM and a CC 50 250 value of 2.705 µM [82] . HCoV-OC43, HCoVNL63, SARS-CoV, and MERS-CoV. Although the mechanism of VAL 346 against certain viruses has not been reported, such as SARS-CoV, HCoV-OC43, and HCoV-347 NL63, its mechanism on some specific viruses has been described in the relevant summary. J o u r n a l P r e -p r o o f SARS molecular epidemiology: a Chinese fairy tale of controlling an emerging zoonotic 433 disease in the genomics era SARS: clinical features and diagnosis Clinical presentations and outcome of 436 severe acute respiratory syndrome in children The severe acute respiratory syndrome Severe acute respiratory syndrome Epidemiology and cause of severe acute 441 respiratory syndrome (SARS) in Guangdong, People's Republic of China Coronavirus: covid-19 has killed more people than SARS and MERS combined Deciphering the biosynthetic codes for the potent anti-SARS-CoV 467 cyclodepsipeptide valinomycin in Streptomyces tsusimaensis ATCC 15141 Small molecules targeting severe 470 acute respiratory syndrome human coronavirus über antibiotica aus 472 actinomyceten How valinomycin ionophores enter 474 and transport K+ across model lipid bilayer membranes Mitochondrial inner membrane depolarization as a marker of platelet apoptosis: disclosure of 477 nonapoptotic membrane depolarization Improved methods of synthesis of valinomycins Type II thioesterase improves 524 heterologous biosynthesis of valinomycin in Escherichia coli SKP2 attenuates 526 autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection Chemical genetics approach to restoring 529 p27Kip1 reveals novel compounds with antiproliferative activity in prostate cancer cells High-throughput screening and 532 identification of potent broad-spectrum inhibitors of coronaviruses Novel ionophores 534 active against La Crosse virus identified through rapid antiviral screening Viruses and 537 bacteria in the etiology of the common cold Complete genomic 539 sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent 540 zoonotic coronavirus transmission event New human coronavirus, HCoV-NL63, 542 associated with severe lower respiratory tract disease in Australia Human coronavirus NL63 544 infection in Canada Human infection with the virus of vesicular stomatitis during an epizootic Entry of poliovirus into cells is blocked by valinomycin and concanamycin 556 A Targeting intracellular ion 558 homeostasis for the control of respiratory syncytial virus Association of hepatitis B virus 561 polymerase with promyelocytic leukemia nuclear bodies mediated by the S100 family protein p11 Productivity losses related to the common cold Human rhinovirus type 2 uncoating at the plasma membrane Bunyavirus requirement for 582 endosomal K + reveals new roles of cellular ion channels during infection Reduced toxicity and enhanced antitumor effects in mice of the ionophoric 585 drug valinomycin when incorporated in liposomes An antifungal agent identical with valinomycin Site-dependent 589 biological activity of valinomycin analogs bearing derivatizable hydroxyl sites Selective synthesis of 592 hydroxy analogues of valinomycin using dioxiranes Recent progress in understanding 2019 594 novel coronavirus (SARS-CoV-2) associated with human respiratory disease: detection, 595 mechanism and treatment Remdesivir and chloroquine effectively 597 inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Human coronavirus Year Type Host Cellular Receptor References HCoV-229E 1965 α-CoV Bats HAPN HCoV-OC43 1967 β-CoV Cattle 9 CoV Palm Civets, Bats ACE2 HCoV-NL63 2004 α-CoV Palm Civets, Bats ACE2 HCoV-HKU1 2005 β-CoV Mice 9-O-Acetylated sialic acid CoV Camels SARS-CoV-2 2019 β-CoV Pangolin Human coronavirus; SARS-CoV: Severe acute respiratory syndrome 601 coronavirus; MERS-CoV: Middle East respiratory syndrome coronavirus; SARS-CoV-2: Severe acute 602 respiratory syndrome coronavirus 2; α-CoV: alphacoronaviruses; β-CoV: betacoronaviruses