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Svensson, Richard
Publications (10 of 26) Show all publications
Ladds, M. J. G., van Leeuwen, I. M. M., Drummond, C. J., Chu, S., Healy, A. R., Popova, G., . . . Lain, S. (2018). A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage. Nature Communications, 9, Article ID 1107.
Open this publication in new window or tab >>A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1107Article in journal (Refereed) Published
Abstract [en]

The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-351427 (URN)10.1038/s41467-018-03441-3 (DOI)000427591600007 ()29549331 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Childhood Cancer FoundationWellcome trust, 073915NIH (National Institute of Health), R01 CA95684
Available from: 2018-06-01 Created: 2018-06-01 Last updated: 2018-08-28Bibliographically approved
Skogh, A., Lesniak, A., Sköld, C., Karlgren, M., Gaugaz, F. Z., Svensson, R., . . . Johansson, A. (2018). An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice. Bioorganic & Medicinal Chemistry Letters, 28(14), 2446-2450
Open this publication in new window or tab >>An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice
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2018 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 14, p. 2446-2450Article in journal (Refereed) Published
Abstract [en]

The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343682 (URN)10.1016/j.bmcl.2018.06.009 (DOI)000438467200020 ()29929882 (PubMedID)
Funder
Swedish Research Council, 9459
Note

Title in dissertation reference list: An Imidazole-Based H-Phe-Phe-NH2 Peptidomimetic with Anti-Allodynic Effect in Spared Nerve Injury Mice and without Neurotoxic Liability

Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-09-24Bibliographically approved
Islam, M. K. K., Strand, M., Saleeb, M., Svensson, R., Baranczewski, P., Artursson, P., . . . Evander, M. (2018). Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound. Scientific Reports, 8, Article ID 1925.
Open this publication in new window or tab >>Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 1925Article in journal (Refereed) Published
Abstract [en]

Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-346222 (URN)10.1038/s41598-018-20362-9 (DOI)000423663100004 ()29386590 (PubMedID)
Funder
Swedish Research Council, 2016-06251
Available from: 2018-03-19 Created: 2018-03-19 Last updated: 2018-03-19Bibliographically approved
Ladds, M. J. G., Pastor-Fernandez, A., Popova, G., van Leeuwen, I. M. M., Eng, K. E., Drummond, C. J., . . . Lain, S. (2018). Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib. PLoS ONE, 13(4), Article ID e0195956.
Open this publication in new window or tab >>Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0195956Article in journal (Refereed) Published
Abstract [en]

Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.

National Category
Microbiology
Identifiers
urn:nbn:se:uu:diva-355471 (URN)10.1371/journal.pone.0195956 (DOI)000430660600026 ()29684045 (PubMedID)
Funder
Swedish Research Council, 521-2014-3341Swedish Research Council, 538-2013-8807Swedish Research Council, 621-2014-4718
Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-06-29Bibliographically approved
Spahiu, L., Alander, J., Ottosson-Wadlund, A., Svensson, R., Lehmer, C., Armstrong, R. N. & Morgenstern, R. (2017). Global Kinetic Mechanism of Microsomal Glutathione Transferase 1 and Insights into Dynamic Enzyme Activation. Biochemistry, 56(24), 3089-3098
Open this publication in new window or tab >>Global Kinetic Mechanism of Microsomal Glutathione Transferase 1 and Insights into Dynamic Enzyme Activation
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2017 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, no 24, p. 3089-3098Article in journal (Refereed) Published
Abstract [en]

Microsomal glutathione transferase 1 (MGST1) has a unique ability to be activated, <= 30-fold, by modification with sulfhydryl reagents. MGST1 exhibits one-third-of-the-sites reactivity toward glutathione and hence heterogeneous binding to different active sites in the homotrimer. Limited turnover stopped-flow kinetic measurements of the activated enzyme allowed us to more accurately determine the KD for the "third" low-affinity GSH binding site (1.4 +/- 0.3 mM). The rate of thiolate formation, k(2) (0.77 +/- 0.06 s(-1)), relevant to turnover, could also be determined. By deriving the steadystate rate equation for a random sequential mechanism for MGST1, we can predict K-M, k(cat), and k(cat)/K-M values from these and previously determined pre-steady-state rate constants (all determined at 5 C). To assess whether the pre-steady-state behavior can account for the steady-state kinetic behavior, we have determined experimental values for kinetic parameters at 5 degrees C. For reactive substrates and the activated enzyme, data for the microscopic steps account for the global mechanism of MGST1. For the unactivated enzyme and more reactive electrophilic substrates, pre steady -state and steady-state data can be reconciled only if a more active subpopulation of MGST1 is assumed. We suggest that unactivated MGST1 can be partially activated in its unmodified form. The existence of an activated subpopulation (approximately 10%) could be demonstrated in limited turnover experiments. We therefore suggest that MSGT1 displays a preexisting dynamic equilibrium between high- and low-activity forms.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-329656 (URN)10.1021/acs.biochem.7b00285 (DOI)000404086000011 ()28558199 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Carl Tryggers foundation
Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2017-09-20Bibliographically approved
Skogh, A., Lesniak, A., Gaugaz, F. Z., Svensson, R., Lindeberg, G., Fransson, R., . . . Sandström, A. (2017). Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration. European Journal of Pharmaceutical Sciences, 109, 533-540, Article ID S0928-0987(17)30497-9.
Open this publication in new window or tab >>Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration
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2017 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 109, p. 533-540, article id S0928-0987(17)30497-9Article in journal (Refereed) Published
Abstract [en]

Substance P 1-7 (SP1-7, Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7) is the major bioactive metabolite formed after proteolytic degradation of the tachykinin substance P (SP). This heptapeptide often opposes the effects of the mother peptide. Hence, SP1-7 is having anti-inflammatory, anti-nociceptive and anti-hyperalgesic effects in experimental models. Despite all encouraging properties of SP1-7 its exact mode of action has not yet been elucidated which has hampered further development of this heptapeptide in drug discovery. Contrary to SP that mediates its biological activity via the NK-1 receptor, the N-terminal fragment SP1-7 acts through an unknown target that is distinct from all known opioid and tachykinin receptors. The SP1-7 amide 1 (Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-NH2) was previously shown to be superior to the endogenous SP1-7 in all experimental pain models where the two compounds were compared. Herein, we report that N-methylation scan of the backbone of the SP1-7 amide (1) results in peptides that are significantly less prone to undergo proteolysis in plasma from both mouse and human. However, with the two exceptions of the [MeLys3]SP1-7 amide (3) and the [MeGln5]SP1-7 amide (4), the peptides with a methyl group attached to the backbone are devoid of significant anti-allodynic effects after peripheral administration in the spared nerve injury (SNI) mouse model of neuropathic pain. It is suggested that the N-methylation does not allow these peptides to form the accurate bioactive conformations or interactions required for efficient binding to the macromolecular target. The importance of intact N-terminal Arg1 and C-terminal Phe7, anticipated to serve as address and message residues, respectively, for achieving the anti-allodynic effect is emphasized. Notably, the three heptapeptides: the SP1-7 amide (1), the [MeLys3]SP1-7 amide (3) amide and the [MeGln5]SP1-7 amide (4) are all considerably more effective in the SNI mouse model than gabapentin that is widely used in the clinic for treatment of neuropathic pain.

Keywords
Anti-allodynia, N-methylation, SP(1–7) amide, Solid phase peptide synthesis (SPPS), Spared nerve injury (SNI), Substance P (SP)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-335651 (URN)10.1016/j.ejps.2017.09.007 (DOI)000413325000055 ()28887235 (PubMedID)
Funder
Swedish Research Council, 9459The Swedish Brain FoundationBerzelii Centre EXSELENT
Available from: 2017-12-07 Created: 2017-12-07 Last updated: 2018-02-28
Skogh, A., Lesniak, A., Gaugaz, F. Z., Svensson, R., Lindeberg, G., Fransson, R., . . . Sandström, A. (2017). Importance of N-and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration. European Journal of Pharmaceutical Sciences, 106, 345-351
Open this publication in new window or tab >>Importance of N-and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration
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2017 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 106, p. 345-351Article in journal (Refereed) Published
Abstract [en]

The heptapeptide SP1-7 (1, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)) is the major bioactive metabolite formed after proteolytic processing of the neuropeptide substance P (SP, Arg(1)-Pro(2)-Lys(3)-Pro(4)-GIn(5)-Gln(6)-Phe(7)-Phe(8)-Gly(9)-Leu(10)-Meti(11)-NH2). The heptapeptide 1 frequently exhibits opposite effects to those induced by SP, such as exerting antinociception, or attenuating thermal hyperalgesia and mechanical allodynia. The heptapeptide SP1-7 amide (2, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)-NH2 ) is often more efficacious than 1 in experimental pain models. We have now assessed the anti-allodynic outcome after systemic administration of 2 and a series of Ala substituted and truncated analogues of 2, in the spared nerve injury (SNI) mice model and the results obtained were correlated with in vitro plasma stability and permeability measurements. It is herein demonstrated that an intact Arg(1) in SP1-7 amide analogues is fundamental for retaining a potent in vivo effect, while Lys(3) of 2 is less important. A displacement with Ala(1) or truncation rendered the peptide analogues either inactive or with a significantly attenuated in vivo activity. Thus, the pentapeptide SP3-7 amide (7, t(1/2) = 11.1 min) proven to be the major metabolite of 2, demonstrated an in vivo effect itself although considerably less significant than 2 in the SNI model. Intraperitoneal administration of 2 in a low dose furnished the most powerful anti-allodynic effect in the SNI model of all the analogous evaluated, despite a fast proteolysis of 2 in plasma (t(1/2) = 6.4 min). It is concluded that not only the C-terminal residue, that we previously demonstrated, but also the N-terminal with its basic side chain, are important for achieving effective pain relief. This information is of value for the further design process aimed at identifying more drug-like SP1-7 amide related peptidomimetics with pronounced antiallodynic effects.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Neuropathic pain, Spared nerve injury (SNI), SP1-7, Neuropeptides, Plasma stability, Structure-activity relationship, Message-address concept
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-334033 (URN)10.1016/j.ejps.2017.06.004 (DOI)000406988600036 ()28587787 (PubMedID)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-02-28Bibliographically approved
Svensson, R. (2017). N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors.. Journal of enzyme inhibition and medicinal chemistry (Print)
Open this publication in new window or tab >>N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors.
2017 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374Article in journal (Refereed) Published
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-343214 (URN)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26
Llona-Minguez, S., Höglund, A., Jacques, S. A., Johanson, L., Calderon-Montano, J. M., Claesson, M., . . . Helleday, T. (2016). Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1. Journal of Medicinal Chemistry, 59(3), 1140-1148
Open this publication in new window or tab >>Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1
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2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 3, p. 1140-1148Article in journal (Refereed) Published
Abstract [en]

The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell sternness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-280245 (URN)10.1021/acs.jmedchem.5b01741 (DOI)000370212700023 ()26771665 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilSwedish Cancer SocietyEU, European Research CouncilSwedish Childhood Cancer FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineCarl Tryggers foundation Wenner-Gren FoundationsTorsten Söderbergs stiftelse
Available from: 2016-03-09 Created: 2016-03-09 Last updated: 2018-01-10Bibliographically approved
Good, J. A. D., Silver, J., Nunez-Otero, C., Bahnan, W., Krishnan, K. S., Salin, O., . . . Almqvist, F. (2016). Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity. Journal of Medicinal Chemistry, 59(5), 2094-2108
Open this publication in new window or tab >>Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity
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2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, p. 2094-2108Article in journal (Refereed) Published
Abstract [en]

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 <= 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 mu M. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-283770 (URN)10.1021/acs.jmedchem.5b01759 (DOI)000372043400031 ()26849778 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Foundation for Strategic Research The Kempe FoundationsSwedish Society for Medical Research (SSMF)
Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2018-01-10Bibliographically approved
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