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Petzold, Katja
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Publications (10 of 18) Show all publications
Makatini, M. M., Petzold, K., Alves, C. N., Arvidsson, P. I., Honarparvar, B., Govender, P., . . . Soliman, M. E. (2013). Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors. Journal of enzyme inhibition and medicinal chemistry (Print), 28(1), 78-88
Open this publication in new window or tab >>Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors
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2013 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 28, no 1, p. 78-88Article in journal (Refereed) Published
Abstract [en]

In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC(50) values ranging from 0.5 up to 0.75 µM against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC(50)(0.5 µM), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC(50) values (0.5-10 µM). The PCU-peptides and peptoides were several orders less toxic (145 μM for 11 and 102 μM for 11 peptoid) to human MT-4 cells than lopinavir (0.025 μM). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-80014 (URN)10.3109/14756366.2011.633907 (DOI)000313663400010 ()22339087 (PubMedID)
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2018-06-08Bibliographically approved
Honarparvar, B., Makatini, M. M., Pawar, S. A., Petzold, K., Soliman, M. E., Arvidsson, P. I., . . . Kruger, H. G. (2012). Pentacycloundecane-diol-based HIV-1 protease inhibitors: biological screening, 2D NMR, and molecular simulation studies. ChemMedChem, 7(6), 1009-1019
Open this publication in new window or tab >>Pentacycloundecane-diol-based HIV-1 protease inhibitors: biological screening, 2D NMR, and molecular simulation studies
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2012 (English)In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 7, no 6, p. 1009-1019Article in journal (Refereed) Published
Abstract [en]

Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC(50) values in the 0.5-0.6 μM range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space (1)H,(1)H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-80015 (URN)10.1002/cmdc.201100512 (DOI)000304438900007 ()22544389 (PubMedID)
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2018-06-08Bibliographically approved
Makatini, M. M., Petzold, K., Arvidsson, P. I., Honarparvar, B., Govender, T., Maguire, G. E., . . . Kruger, H. G. (2012). Synthesis, screening and computational investigation of pentacycloundecane-peptoids as potent CSA-HIV PR inhibitors. European Journal of Medicinal Chemistry, 57, 459-467
Open this publication in new window or tab >>Synthesis, screening and computational investigation of pentacycloundecane-peptoids as potent CSA-HIV PR inhibitors
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2012 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 57, p. 459-467Article in journal (Refereed) Published
Abstract [en]

Herein, we present the first pentacycloundecane (PCU) diol peptoid derived HIV protease inhibitors with IC(50) values ranging from 6.5 to 0.075 μM. Five derivatives were synthesized in an attempt to understand the structure activity relationship of this class of compounds for HIV protease inhibition. NMR spectroscopy (new Efficient Adiabatic Symmetrized Rotating Overhauser Effect Spectroscopy, EASY-ROESY) was employed to determine the predominant conformation of the active compound. In this study docking studies and MD simulations provided insight into the binding theme of this class of peptoid inhibitors to the CSA-HIV PR active site. Conserved and stable hydrogen bonding between the hydroxyl groups of the inhibitors and the active site Asp25/Asp25' residues were observed from the docking and along the MD trajectories.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-80016 (URN)10.1016/j.ejmech.2012.06.019 (DOI)000312621700047 ()22867528 (PubMedID)
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2018-06-08Bibliographically approved
Dethoff, E. A., Petzold, K., Chugh, J., Casiano-Negroni, A. & Al-Hashimi, H. M. (2012). Visualizing transient low-populated structures of RNA. Nature, 491(7426), 724-728
Open this publication in new window or tab >>Visualizing transient low-populated structures of RNA
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2012 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7426, p. 724-728Article in journal (Refereed) Published
Abstract [en]

The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captured by structure characterization techniques. Here we report the nuclear magnetic resonance visualization of RNA transitions towards 'invisible' excited states (ESs), which exist in too little abundance (2-13%) and for too short a duration (45-250 μs) to allow structural characterization by conventional techniques. Transitions towards ESs result in localized rearrangements in base-pairing that alter building block elements of RNA architecture, including helix-junction-helix motifs and apical loops. The ES can inhibit function by sequestering residues involved in recognition and signalling or promote ATP-independent strand exchange. Thus, RNAs do not adopt a single conformation, but rather exist in rapid equilibrium with alternative ESs, which can be stabilized by cellular cues to affect functional outcomes.

National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-80012 (URN)10.1038/nature11498 (DOI)23041928 (PubMedID)
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2018-06-08Bibliographically approved
Makatini, M. M., Petzold, K., Sriharsha, S. N., Soliman, M. E., Honarparvar, B., Arvidsson, P. I., . . . Govender, T. (2011). Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease. Bioorganic & Medicinal Chemistry Letters, 21(8), 2274-2277
Open this publication in new window or tab >>Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease
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2011 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 21, no 8, p. 2274-2277Article in journal (Refereed) Published
Abstract [en]

In this study, we present the first account of pentacycloundecane (PCU) peptide based HIV-protease inhibitors. The inhibitor exhibiting the highest activity made use of a natural HIV-protease substrate peptide sequence, that is, attached to the cage (PCU-EAIS). This compound showed nanomolar IC(50) activity against the resistance-prone wild type C-South African HIV-protease (C-SA) catalytic site via a norstatine type functional group of the PCU hydroxy lactam. NMR was employed to determine a logical correlation between the inhibitory concentration (IC(50)) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. The results from docking experiments coincided with the experimental observed activities. These findings open up useful applications for this family of cage peptide inhibitors, considering the vast number of alternative disease related proteases that exist.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-80019 (URN)10.1016/j.bmcl.2011.02.105 (DOI)000289074700020 ()21429747 (PubMedID)
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2018-06-08Bibliographically approved
Petzold, K. & Al-Hashimi, H. M. (2011). RNA structure: adding a second dimension. Nature Chemistry, 3(12), 913-915
Open this publication in new window or tab >>RNA structure: adding a second dimension
2011 (English)In: Nature Chemistry, ISSN 1755-4330, E-ISSN 1755-4349, Vol. 3, no 12, p. 913-915Article in journal (Refereed) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-80013 (URN)10.1038/nchem.1209 (DOI)22109268 (PubMedID)
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2018-06-08Bibliographically approved
Shaikh, M., Petzold, K., Kruger, H. & du Toit, K. (2011). Synthesis and NMR elucidation of homoisoflavanone analogues. Structural Chemistry, 22(1), 161-166
Open this publication in new window or tab >>Synthesis and NMR elucidation of homoisoflavanone analogues
2011 (English)In: Structural Chemistry, ISSN 1040-0400, E-ISSN 1572-9001, Vol. 22, no 1, p. 161-166Article in journal (Refereed) Published
Abstract [en]

A series of five homoisoflavanone analogues have been synthesized from the corresponding 3,5-methoxy phenols via chroman-4-one in three steps. The complete NMR elucidation of these homoisoflavanone analogues is reported. The use of 2D NMR techniques (COSY, NOESY, HSQC and HMBC) proved to be very useful tools in the elucidation of homoisoflavanone analogues. The homoisoflavanone analogues exhibit an AA'BB' spin pattern in the ring B of the homoisoflavanone. These homoisoflavanone analogues are potential antifungal and anti-inflammatory agents.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-80018 (URN)10.1007/s11224-010-9703-x (DOI)000286983500019 ()
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2018-06-08Bibliographically approved
Makatini, M. M., Petzold, K., Sriharsha, S. N., Ndlovu, N., Soliman, M. E., Honarparvar, B., . . . Govender, T. (2011). Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: a hybrid 2D NMR and docking/QM/MM/MD approach. European Journal of Medicinal Chemistry, 46(9), 3976-3985
Open this publication in new window or tab >>Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: a hybrid 2D NMR and docking/QM/MM/MD approach
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2011 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 46, no 9, p. 3976-3985Article in journal (Refereed) Published
Abstract [en]

Pentacycloundecane (PCU) lactam-peptide based HIV protease inhibitors were synthesized and nanomolar activity against the resistance-prone wild type C-South African HIV protease is reported. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. EASY-ROESY NMR experiments gave information about the 3D structure of the cage peptides and 3D solution structure could be linked to the experimental IC(50) activity profile of the considered inhibitors. QM/MM/MD simulations of the inhibitors in solution confirmed the NMR observed conformations. Docking experiments and QM/MM/MD simulations of the inhibitor-HIV PR complexes were also performed. These computational results complimented the experimental inhibition activities and enabled us to report a unique binding mode for PCU-based inhibitors at the active site of HIV-protease enzyme. A conserved hydrogen bonding pattern between the norstatine type functional group of the PCU hydroxylactam and active site residues, ASP25/ASP25', was observed in all active compounds. The biological significance and possible mode of inhibition by PCU-based HIV PR inhibitors discussed herein provide us with a deeper understanding of the mode of action of these novel inhibitors. The PCU-peptides are between 6000 and 8500 time less toxic to human MT-4 cells than Lopinavir. This potentially creates new application avenues for these putative inhibitors to be investigated against a vast number of other disease-related proteases.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-80017 (URN)10.1016/j.ejmech.2011.05.071 (DOI)000295237400046 ()21741133 (PubMedID)
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2018-06-08Bibliographically approved
Olofsson, A., Vallström, A., Petzold, K., Tegtmeyer, N., Schleucher, J., Carlsson, S., . . . Arnqvist, A. (2010). Biochemical and functional characterization of Helicobacter pylori vesicles. Molecular Microbiology, 77(6), 1539-1555
Open this publication in new window or tab >>Biochemical and functional characterization of Helicobacter pylori vesicles
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2010 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 77, no 6, p. 1539-1555Article in journal (Refereed) Published
Abstract [en]

Helicobacter pylori can cause peptic ulcer disease and/or gastric cancer. Adhesion of bacteria to the stomach mucosa is an important contributor to the vigor of infection and resulting virulence. H. pylori adheres primarily via binding of BabA adhesins to ABO/Lewis b (Leb) blood group antigens and the binding of SabA adhesins to sialyl-Lewis x/a (sLex/a) antigens. Similar to most Gram-negative bacteria, H. pylori continuously buds off vesicles and vesicles derived from pathogenic bacteria often include virulence-associated factors. Here we biochemically characterized highly purified H. pylori vesicles. Major protein and phospholipid components associated with the vesicles were identified with mass spectroscopy and NMR. A subset of virulence factors present was confirmed by immunoblots. Additional functional and biochemical analysis focused on the vesicle BabA and SabA adhesins and their respective interactions to human gastric epithelium. Vesicles exhibit heterogeneity in their protein composition, which were specifically studied in respect to the BabA adhesin. We also demonstrate that the oncoprotein, CagA, is associated with the surface of H. pylori vesicles. Thus, we have explored mechanisms for intimate H. pylori vesicle-host interactions and found that the vesicles carry effector-promoting properties that are important to disease development.

Place, publisher, year, edition, pages
Wiley, 2010
Identifiers
urn:nbn:se:umu:diva-35586 (URN)10.1111/j.1365-2958.2010.07307.x (DOI)000281831400018 ()20659286 (PubMedID)
Available from: 2010-08-24 Created: 2010-08-24 Last updated: 2018-06-08Bibliographically approved
Thiele, C. M., Petzold, K. & Schleucher, J. (2009). EASY ROESY: reliable cross-peak integration in adiabatic symmetrized ROESY. Chemistry - A European Journal, 15(3), 585-588
Open this publication in new window or tab >>EASY ROESY: reliable cross-peak integration in adiabatic symmetrized ROESY
2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 3, p. 585-588Article in journal (Refereed) Published
Abstract [en]

Estimates of intramolecular distances are essential for structure determination. For medium-sized molecules, ROESY NMR is the method of choice for obtaining distances. However, the integration of ROESY cross-peaks is problematic due to the offset dependence of theintegrals and/or TOCSY artefacts. We here present EASY ROESY (rEliable Adiabatic SYmmetrized ROESY), which yields reliable intramolecular distances without sample-specific setup.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-25735 (URN)10.1002/chem.200802027 (DOI)
Available from: 2009-09-01 Created: 2009-09-01 Last updated: 2018-06-08Bibliographically approved

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