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001-es BibID:BIBFORM086717
Első szerző:Golda Mária (molekuláris biológus)
Cím:Study of the Retrotransposon-Derived Human PEG10 Protease / Mária Golda, János András Mótyán, Mohamed Mahdi, József Tőzsér
Dátum:2020
Megjegyzések:Paternally expressed gene 10 (PEG10) is a human retrotransposon-derived imprinted gene. Previous works have demonstrated that a mutation in the coding sequence of this gene is lethal with regard to embryological age due to defects of placental development. In addition, PEG10 is implicated in several malignancies, such as pancreatic cancer and hepatocellular carcinoma. The PEG10 gene encodes two protein isoforms, which are translated by a typical retroviral frameshift mechanism. The Gag-like protein (RF1PEG10) is encoded by reading frame 1, whilst reading frames 1 and 2 accounts for the Gag-Pol-like polyprotein (RF1/RF2PEG10). The protease (PR) domain of RF2PEG10 contains an -Asp-Ser-Gly- sequence, which refers to the conservative -Asp-Ser/Thr-Gly- active-site motif of retroviral aspartic proteases. The function of the aspartic protease domain of RF2PEG10 remains unclear. In order to further investigate the function of the PEG10 protease (PRPEG10), a frameshift mutant was generated (fsRF1/RF2PEG10) for comparison with the RF1/RF2PEG10 form. To study the effects of PRPEG10 on cellular proliferation and viability, mammalian HEK293T and HaCaT cells were transfected with plasmids encoding for either the frameshift mutant (fsRF1/RF2PEG10) or a PR active-site (D370A) mutant fsRF1/RF2PEG10. Based on our findings, an fsRF1/RF2PEG10 overexpression resulted in an increased cellular proliferation, compared to the mutant form. Interestingly, transfection with fsRF1/RF2PEG10 had a detrimental effect on cell viability. We hypothesize that PRPEG10 may play a cardinal role in the function of this retroviral remnant, possibly implicated in cellular proliferation and the inhibition of apoptosis.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idézhető absztrakt
folyóiratcikk
PEG10
paternally expressed gene 10
cell viability
cell proliferation
cis protease activity
ubiquitination
homology modeling
retroviral-like protease
retrotransposon
protease
Megjelenés:Proceedings. - 50 : 1 (2020), p. 110. -
További szerzők:Mótyán János András (1981-) (biokémikus, molekuláris biológus) Mahdi, Mohamed (1979-) (orvos, tudományos segédmunkatárs) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:GINOP-2.3.2-15-2016-00044
GINOP
K-101591
OTKA
NKFIH-1150-6/2019
Egyéb
NKFI-125238
Egyéb
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DOI
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2.

001-es BibID:BIBFORM084537
035-os BibID:(scopus)85083042118 (wos)000535574200166
Első szerző:Golda Mária (molekuláris biológus)
Cím:Functional Study of the Retrotransposon-Derived Human PEG10 Protease / Mária Golda, János András Mótyán, Mohamed Mahdi, József Tőzsér
Dátum:2020
ISSN:1661-6596 1422-0067
Megjegyzések:Paternally expressed gene 10 (PEG10) is a human retrotransposon-derived imprinted gene. The mRNA of PEG10 encodes two protein isoforms: the Gag-like protein (RF1PEG10) is coded by reading frame 1, while the Gag-Pol-like polyprotein (RF1/RF2PEG10) is coded by reading frames 1 and 2. The proteins are translated by a typical retroviral frameshift mechanism. The protease (PR) domain of RF2PEG10 contains an -Asp-Ser-Gly- sequence, which corresponds to the consensus -Asp-Ser/Thr-Gly- active-site motif of retroviral aspartic proteases. The function of the aspartic protease domain of RF2PEG10 remains unclear. To elucidate the function of PEG10 protease (PRPEG10), we designed a frameshift mutant (fsRF1/RF2PEG10) for comparison with the RF1/RF2PEG10 form. To study the effects of PRPEG10 on cellular proliferation and viability, mammalian HEK293T and HaCaT cells were transfected with plasmids coding for either RF1/RF2PEG10, the frameshift mutant (fsRF1/RF2PEG10), or a PR active-site (D370A) mutant fsRF1/RF2PEG10. Our results indicate that fsRF1/RF2PEG10 overexpression results in increased cellular proliferation. Remarkably, transfection with fsRF1/RF2PEG10 had a detrimental effect on cell viability. We hypothesize that PRPEG10 plays an important role in the function of this retroviral remnant, mediating the proliferation of cells and possibly implicating it in the inhibition of apoptosis.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
PEG10
paternally expressed gene 10
cell viability
cell proliferation
cis protease activity
ubiquitination
homology modeling
retroviral-like protease
protease
retrotransposon
aspartic protease
Megjelenés:International Journal Of Molecular Sciences. - 21 : 7 (2020), p. 1-22. -
További szerzők:Mótyán János András (1981-) (biokémikus, molekuláris biológus) Mahdi, Mohamed (1979-) (orvos, tudományos segédmunkatárs) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:GINOP-2.3.2-15-2016-00044
GINOP
101591
OTKA
NKFIH-1150-6/2019
Egyéb
NKFIH-125238
Egyéb
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
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3.

001-es BibID:BIBFORM089444
035-os BibID:(WOS)000595728400003 (Scopus)85096570971
Első szerző:Mahdi, Mohamed (orvos, tudományos segédmunkatárs)
Cím:Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2·s main protease / Mahdi Mohamed, Mótyán János András, Szojka Zsófia Ilona, Golda Mária, Miczi Márió, Tőzsér József
Dátum:2020
ISSN:1743-422X
Megjegyzések:Background: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. For cell culture experiments a dark-to-bright GFP reporter substrate system was designed. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 ?M. None of the inhibitors showed significant inhibition of SARS-CoV-2 Mpro in our in vitro enzymatic assays up to 100 ?M concentration. Conclusion Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
SARS-CoV-2
Inhibition profling
In vitro assay
HIV protease inhibitors
Protease
Megjelenés:Virology Journal. - 17 : 1 (2020), p. 1-8. -
További szerzők:Mótyán János András (1981-) (biokémikus, molekuláris biológus) Szojka Zsófia (1991-) (molekuláris biológus) Golda Mária (1986-) (molekuláris biológus) Miczi Márió Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:NKFIH-1150?6/2019
Egyéb
NKFI 125238
Egyéb
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
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4.

001-es BibID:BIBFORM136091
Első szerző:Mótyán János András (biokémikus, molekuláris biológus)
Cím:Molecular mechanisms of protease precursor autoprocessing of RNA viruses : a comprehensive review / Mótyán János András, Golda Mária, Mahdi Mohamed, Nashed Nashaat T., Louis John M., Tőzsér József
Dátum:2026
ISSN:1743-422X
Megjegyzések:Many viruses express their proteins in the form of large polyproteins comprising structural and non-structural (e.g. enzymatic) units that are released from the precursor through ordered proteolysis. Proteolytic processing of polyproteins is an indispensable regulatory step for virus maturation and replication that is carried out by the virus-encoded and/or cellular proteases. The activity of a viral protease that is expressed as a part of a polyprotein is controlled in part by the self-cleavage (autoprocessing) from the precursor. The mechanism of protease precursor processing has been established at the molecular level for various RNA virus proteases, including human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both viral protease precursors are processed via intra- (in cis) and intermolecular (in trans) cleavages at the N- and C-termini, respectively, yielding the mature enzyme. The remarkably similar activation mechanisms of HIV and SARS-CoV-2 PRs suggest that other viral proteases are activated similarly. In this review, we provide a detailed overview on the protease precursor autoprocessing mechanism of HIV-1 and SARS-CoV-2 proteases and compare those to the activation mechanism of non-viral proteases from their zymogens. Also, we review the activation mechanism of other ss(+)RNA viruses that utilize the polyprotein pathway for their replication. Based on such comparison, it appears that the protease activation mechanisms of most enveloped ss(+)RNA viruses from their precursors share many common features, although they do not correlate directly with the evolutionary relationships, the presence or absence of viral envelope or the catalytic mechanism of the viral protease.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
SARS-CoV-2
HIV-1
HIV virus
Polyprotein
Self-cleavage
Autoprocessing
Protease precursor
Protease
RNA virus
Proteolysis
Megjelenés:Virology Journal. - [Epub ahead of print] (2026). -
További szerzők:Golda Mária (1986-) (molekuláris biológus) Mahdi, Mohamed (1979-) (orvos, tudományos segédmunkatárs) Nashed, Nashaat T. Louis, John M. Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:BO/00110/23/5
MTA
ADVANCED_150532
OTKA
TKP2021-EGA-20
Egyéb
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DOI
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5.

001-es BibID:BIBFORM130745
035-os BibID:(Scopus)105009019976 (wos)001516039100001
Első szerző:Mótyán János András (biokémikus, molekuláris biológus)
Cím:Identification of SARS-CoV-2 Main Protease Cleavage Sites in Bovine β-Casein / Mótyán János András, Nagy Tibor, Nagyné Veres Ágota, Golda Mária, Mahdi Mohamed, Tőzsér József
Dátum:2025
ISSN:1661-6596 1422-0067
Megjegyzések:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease of 2019 (COVID-19) and has persistently caused infections since its emergence in late 2019. The main protease (Mpro) of SARS-CoV-2 plays a crucial role in its life-cycle; thus, it is an important target for drug development. One of the first virus-specific drugs that has been approved for the treatment of COVID-19 patients is Paxlovid, which contains nirmatrelvir, a covalent inhibitor of Mpro. Screening of inhibitor candidates and specificity studies also rely on efficient substrates and activity assays. Casein is one of the most commonly applied universal substrates that can be used to study a wide range of proteases, including SARS-CoV-2 Mpro. Casein is a known substrate for Mpro in vitro, but the specific casein isoform cleaved by Mpro remained unidentified, and the cleavage sites have yet to be determined. This work studied cleavage of ?-, ?- and ?-isoforms of bovine casein by SARS-CoV-2 Mpro, using in vitro and in silico approaches. The candidate cleavage sites were predicted in silico based on the protein sequences, and the cleavage positions were identified based on mass spectrometric analysis of cleavage fragments. Based on our results, only ?-casein contains cleavage sites for Mpro and thus can be used as its substrate in vitro. The newly identified cleavage site sequences further widen the knowledge about the specificity of SARS-CoV-2 Mpro.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
SARS-CoV-2
main protease
coronavirus
casein
protease
cleavage site
substrate specificity
cleavage site prediction
proteolyis
Megjelenés:International Journal Of Molecular Sciences. - 26 : 12 (2025), p. 1-11. -
További szerzők:Nagy Tibor (1988-) (vegyész) Veres Ágota (laboráns) Golda Mária (1986-) (molekuláris biológus) Mahdi, Mohamed (1979-) (orvos, tudományos segédmunkatárs) Tőzsér József (1959-) (molekuláris biológus, biokémikus, vegyész)
Pályázati támogatás:TKP2021-EGA-20
Egyéb
TKP2021-NKTA-34
Egyéb
NKFIH Advanced 150532
Egyéb
BO/00110/23/5
MTA
University of Debrecen (UD) Program for Scientific Publication
Egyéb
UD Faculty of Medicine Research Fund (Bridging fund)
Egyéb
UD Scientific Research Bridging Fund (DETKA)
Egyéb
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DOI
Intézményi repozitóriumban (DEA) tárolt változat
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