PDTC inhibits picornavirus polyprotein processing and RNA replication by transporting zinc ions into cells.
Previously, it was shown that pyrrolidine dithiocarbamate (PDTC) inhibits proteolytic polyprotein processing and replication of human rhinovirus by transporting metal ions into cells. Here, it is shown that PDTC also inhibits replication of two other picornaviruses: coxsackievirus B3 (CVB3), a closely related virus that belongs to the genus Enterovirus, and mengovirus, an encephalomyocarditis virus strain that belongs to the genus Cardiovirus, and that this inhibition is due to the dithiocarbamate moiety of the compound. Making use of subgenomic replicons, evidence is provided that PDTC inhibits replication of these two viruses by disturbing viral RNA synthesis. Furthermore, it is shown that PDTC transports zinc ions into cells and that these zinc ions play an important role in the antiviral activity mediated by PDTC. Finally, it is shown that PDTC interferes with proteolytic processing of the polyproteins of both CVB3 and mengovirus, but that the underlying mechanism between these two viruses differs. In CVB3-infected cells, PDTC interferes strongly with the proteolytic activity of 3CD(pro), as shown by the impaired production of the mature capsid proteins as well as the autocleavage of 3CD(pro) into 3C(pro) and 3D(pol). In mengovirus-infected cells, however, PDTC had no effect on the proteolytic production of capsid proteins or the autocleavage of 3CD(pro). Instead, PDTC caused the accumulation of a high-molecular-mass precursor protein, due to an impairment in the primary 'break' that normally occurs at the 2A-2B junction. Thus, PDTC disturbs polyprotein processing and replication of two groups of picornaviruses, enteroviruses and cardioviruses, but the underlying mechanism is different.
Lanke
K
K
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands.
Krenn
B M
BM
Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Medical Biochemistry, Medical University of Vienna, Dr Bohr Gasse 9/3, A-1030 Vienna, Austria.
Melchers
W J G
WJG
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands.
Seipelt
J
J
Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Medical Biochemistry, Medical University of Vienna, Dr Bohr Gasse 9/3, A-1030 Vienna, Austria.
van Kuppeveld
F J M
FJM
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands.
D000086042:3C Viral Proteases; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003546:Cysteine Endopeptidases; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000502:physiology; D008574:Mengovirus / Q000187:drug effects* / Q000502:physiology; D020815:Polyproteins / Q000096:biosynthesis; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis*; D013859:Thiocarbamates / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects; D015032:Zinc / Q000378:metabolism*
D000998:Antiviral Agents; D020815:Polyproteins; D011759:Pyrrolidines; D012367:RNA, Viral; D013859:Thiocarbamates; D014764:Viral Proteins; C020972:pyrrolidine dithiocarbamic acid; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; D015032:Zinc