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Strand, Mårten
Publications (10 of 10) Show all publications
Islam, K., Carlsson, M., Enquist, P.-A., Qian, W., Marttila, M., Strand, M., . . . Evander, M. (2022). Structural Modifications and Biological Evaluations of Rift Valley Fever Virus Inhibitors Identified from Chemical Library Screening. ACS Omega, 7(8), 6854-6868
Open this publication in new window or tab >>Structural Modifications and Biological Evaluations of Rift Valley Fever Virus Inhibitors Identified from Chemical Library Screening
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2022 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 7, no 8, p. 6854-6868Article in journal (Refereed) Published
Abstract [en]

The Rift Valley fever virus (RVFV) is an emerging high-priority pathogen endemic in Africa with pandemic potential. There is no specific treatment or approved antiviral drugs for the RVFV. We previously developed a cell-based high-throughput assay to screen small molecules targeting the RVFV and identified a potential effective antiviral compound (1-N-(2-(biphenyl-4-yloxy)ethyl)propane-1,3-diamine) as a lead compound. Here, we investigated how structural modifications of the lead compound affected the biological properties and the antiviral effect against the RVFV. We found that the length of the 2-(3-aminopropylamino)ethyl chain of the compound was important for the compound to retain its antiviral activity. The antiviral activity was similar when the 2-(3-aminopropylamino)ethyl chain was replaced with a butyl piperazine chain. However, we could improve the cytotoxicity profile of the lead compound by changing the phenyl piperazine linker from the para-position (compound 9a) to the meta-position (compound 13a). Results from time-of-addition studies suggested that compound 13a might be active during virus post-entry and/or the replication phase of the virus life cycle and seemed to affect the K+ channel. The modifications improved the properties of our lead compound, and our data suggest that 13a is a promising candidate to evaluate further as a therapeutic agent for RVFV infection.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2022
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-192961 (URN)10.1021/acsomega.1c06513 (DOI)000823310600001 ()2-s2.0-85125402166 (Scopus ID)
Funder
Swedish Research Council, 2016-06251Familjen Erling-Perssons StiftelseRegion Västerbotten
Available from: 2022-03-07 Created: 2022-03-07 Last updated: 2023-09-05Bibliographically approved
Gwon, Y.-D., Strand, M., Lindquist, R., Nilsson, E., Saleeb, M., Elofsson, M., . . . Evander, M. (2020). Antiviral Activity of Benzavir-2 against Emerging Flaviviruses. Viruses, 12(3), Article ID 351.
Open this publication in new window or tab >>Antiviral Activity of Benzavir-2 against Emerging Flaviviruses
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2020 (English)In: Viruses, E-ISSN 1999-4915, Vol. 12, no 3, article id 351Article in journal (Refereed) Published
Abstract [en]

Most flaviviruses are arthropod-borne viruses, transmitted by either ticks or mosquitoes, and cause morbidity and mortality worldwide. They are endemic in many countries and have recently emerged in new regions, such as the Zika virus (ZIKV) in South-and Central America, the West Nile virus (WNV) in North America, and the Yellow fever virus (YFV) in Brazil and many African countries, highlighting the need for preparedness. Currently, there are no antiviral drugs available to treat flavivirus infections. We have previously discovered a broad-spectrum antiviral compound, benzavir-2, with potent antiviral activity against both DNA- and RNA-viruses. Our purpose was to investigate the inhibitory activity of benzavir-2 against flaviviruses. We used a ZIKV ZsGreen-expressing vector, two lineages of wild-type ZIKV, and other medically important flaviviruses. Benzavir-2 inhibited ZIKV derived reporter gene expression with an EC50 value of 0.8 +/- 0.1 µM. Furthermore, ZIKV plaque formation, progeny virus production, and viral RNA expression were strongly inhibited. In addition, 2.5 µM of benzavir-2 reduced infection in vitro in three to five orders of magnitude for five other flaviviruses: WNV, YFV, the tick-borne encephalitis virus, Japanese encephalitis virus, and dengue virus. In conclusion, benzavir-2 was a potent inhibitor of flavivirus infection, which supported the broad-spectrum antiviral activity of benzavir-2.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
benzavir-2, flavivirus, Zika virus, antiviral drugs
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-174282 (URN)10.3390/v12030351 (DOI)000525486800013 ()32235763 (PubMedID)2-s2.0-85082528703 (Scopus ID)
Funder
Swedish Research Council, 2016–06251
Available from: 2020-08-20 Created: 2020-08-20 Last updated: 2024-01-17Bibliographically 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, 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
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-144950 (URN)10.1038/s41598-018-20362-9 (DOI)000423663100004 ()29386590 (PubMedID)2-s2.0-85041677376 (Scopus ID)
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2023-03-24Bibliographically approved
Ianevski, A., Zusinaite, E., Kuivanen, S., Strand, M., Lysvand, H., Teppor, M., . . . Kainov, D. (2018). Novel activities of safe-in-human broad-spectrum antiviral agents. Antiviral Research, 154, 174-182
Open this publication in new window or tab >>Novel activities of safe-in-human broad-spectrum antiviral agents
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2018 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 154, p. 174-182Article in journal (Refereed) Published
Abstract [en]

According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-inhuman antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases.

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-150889 (URN)10.1016/j.antiviral.2018.04.016 (DOI)000433651300021 ()29698664 (PubMedID)2-s2.0-85046170096 (Scopus ID)
Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-08-17Bibliographically approved
Strand, M., Carlsson, M., Uvell, H., Islam, K., Edlund, K., Cullman, I., . . . Almqvist, F. (2014). Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria. Marine Drugs, 12(2), 799-821
Open this publication in new window or tab >>Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria
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2014 (English)In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 12, no 2, p. 799-821Article in journal (Refereed) Published
Abstract [en]

Adenovirus infections in immunocompromised patients are associated with high mortality rates. Currently, there are no effective anti-adenoviral therapies available. It is well known that actinobacteria can produce secondary metabolites that are attractive in drug discovery due to their structural diversity and their evolved interaction with biomolecules. Here, we have established an extract library derived from actinobacteria isolated from Vestfjorden, Norway, and performed a screening campaign to discover anti-adenoviral compounds. One extract with anti-adenoviral activity was found to contain a diastereomeric 1:1 mixture of the butenolide secondary alcohols 1a and 1b. By further cultivation and analysis, we could isolate 1a and 1b in different diastereomeric ratio. In addition, three more anti-adenoviral butenolides 2, 3 and 4 with differences in their side-chains were isolated. In this study, the anti-adenoviral activity of these compounds was characterized and substantial differences in the cytotoxic potential between the butenolide analogs were observed. The most potent butenolide analog 3 displayed an EC50 value of 91 μM and no prominent cytotoxicity at 2 mM. Furthermore, we propose a biosynthetic pathway for these compounds based on their relative time of appearance and structure.

Place, publisher, year, edition, pages
MDPI, 2014
Keywords
adenovirus; antiviral; natural products; secondary metabolites; marine actinobacteria; extract screening; butenolides
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-86525 (URN)10.3390/md12020799 (DOI)000335745100011 ()24477283 (PubMedID)2-s2.0-84896740554 (Scopus ID)
Available from: 2014-03-03 Created: 2014-02-28 Last updated: 2023-03-23Bibliographically approved
Strand, M. (2014). The discovery of antiviral compounds targeting adenovirus and herpes simplex virus: assessment of synthetic compounds and natural products. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>The discovery of antiviral compounds targeting adenovirus and herpes simplex virus: assessment of synthetic compounds and natural products
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a need for new antiviral drugs. Especially for the treatment of adenovirus infections, since no approved anti-adenoviral drugs are available. Adenovirus infections in healthy persons are most often associated with respiratory disease, diarrhea and infections of the eye. These infections can be severe, but are most often self-limiting. However, in immunocompromised patients, adenovirus infections are associated with morbidity and high mortality rates. These patients are mainly stem cell or bone marrow transplantation recipients, however solid organ transplantation recipients or AIDS patients may be at risk as well. In addition, children are at higher risk to develop disseminated disease.

Due to the need for effective anti-adenoviral drugs, we have developed a cell based screening assay, using a replication-competent GFP expressing adenovirus vector based on adenovirus type 11 (RCAd11GFP). This assay facilitates the screening of chemical libraries for antiviral activity. Using this assay, we have screened 9800 small molecules for anti-adenoviral activity with low toxicity. One compound, designated Benzavir-1, was identified with activity against representative types of all adenovirus species. In addition, Benzavir-1 was more potent than cidofovir, which is the antiviral drug used for treatment of adenovirus disease. By structure-activity relationships analysis (SAR), the potency of Benzavir-1 was improved. Hence, the improved compound is designated Benzavir-2. To assess the antiviral specificity, the activity of Benzavir-1 and -2 on both types of herpes simplex virus (HSV) was evaluated. Benzavir-2 displayed better efficacy than Benzavir-1 and had an activity comparable to acyclovir, which is the original antiviral drug used for therapy of herpes virus infections. In addition, Benzavir-2 was active against acyclovir-resistant clinical isolates of both HSV types.

To expand our search for compounds with antiviral activity, we turned to the natural products. An ethyl acetate extract library was established, with extracts derived from actinobacteria isolated from sediments of the Arctic Sea. Using our screening assay, several extracts with anti-adenoviral activity and low toxicity were identified. By activity-guided fractionation of the extracts, the active compounds could be isolated. However, several compounds had previously been characterized with antiviral activity. Nonetheless, one compound had uncharacterized antiviral activity and this compound was identified as a butenolide. Additional butenolide analogues were found and we proposed a biosynthetic pathway for the production of these compounds. The antiviral activity was characterized and substantial differences in their toxic potential were observed. One of the most potent butenolide analogues had minimal toxicity and is an attractive starting point for further optimization of the anti-adenoviral activity.

This thesis describes the discovery of novel antiviral compounds that targets adenovirus and HSV infections, with the emphasis on adenovirus infections. The discoveries in this thesis may lead to the development of new antiviral drugs for clinical use. 

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. p. 104
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1647
Keywords
virology, antiviral, adenovirus, herpes simplex virus, small molecule, inhibitor, hsv, drug discovery
National Category
Microbiology in the medical area Pharmacology and Toxicology Microbiology
Research subject
Medical Virology; computational linguistics; Microbiology
Identifiers
urn:nbn:se:umu:diva-88186 (URN)978-91-7601-043-3 (ISBN)
Public defence
2014-05-16, Betula, by 6M, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 621-2010-4746Swedish Cancer Society, 100356Swedish Research Council, K2007-56X-05688-28-3
Available from: 2014-04-25 Created: 2014-04-24 Last updated: 2018-06-07Bibliographically approved
Strand, M., Islam, K., Edlund, K., Öberg, C. T., Allard, A., Bergström, T., . . . Wadell, G. (2012). 2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 2. Antimicrobial Agents and Chemotherapy, 56(11), 5735-5743
Open this publication in new window or tab >>2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 2
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2012 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 11, p. 5735-5743Article in journal (Refereed) Published
Abstract [en]

Herpes simplex viruses (HSV-1 and HSV-2) are responsible for life-long latent infections in humans, with periods of viral reactivation associated with recurring ulcerations in the orofacial and genital tract. In immunosuppressed patients and neonates, HSV infections are associated with severe morbidity, and in some cases even mortality. Today, acyclovir is the standard therapy for management of HSV infections. However, the need for novel antiviral agents is apparent since HSV isolates resistant to acyclovir therapy are frequently isolated in immunosuppressed patients. In this study, we assessed the anti-HSV activity of the anti-adenoviral compounds 2-[2-(2-benzoylamino)-benzoylamino]benzoic acid, (Benzavir-1) and 2-[4,5-difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, (Benzavir-2) on HSV-1 and HSV-2. Both compounds were active against both viruses. Importantly, Benzavir-2 had similar potency to acyclovir against both HSV types and it was active against clinical acyclovir-resistant HSV isolates.

Place, publisher, year, edition, pages
American Society Microbiology, 2012
Keywords
Herpes simplex virus, HSV, inhibitor, 2-[2-(benzoylamino)benzoylamino]benzoic acid, antiviral, Benzavir
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-60354 (URN)10.1128/AAC.01072-12 (DOI)000310055800039 ()22908173 (PubMedID)2-s2.0-84868007915 (Scopus ID)
Available from: 2012-10-09 Created: 2012-10-09 Last updated: 2023-03-24Bibliographically approved
Öberg, C. T., Strand, M., Andersson, E. K., Edlund, K., Tran, N. P., Mei, Y.-F., . . . Elofsson, M. (2012). Synthesis, biological evaluation, and structure-activity relationships of 2-[2-(benzoylamino)benzoylamino]benzoic acid analogues as inhibitors of adenovirus replication. Journal of Medicinal Chemistry, 55(7), 3170-3181
Open this publication in new window or tab >>Synthesis, biological evaluation, and structure-activity relationships of 2-[2-(benzoylamino)benzoylamino]benzoic acid analogues as inhibitors of adenovirus replication
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2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 7, p. 3170-3181Article in journal (Refereed) Published
Abstract [en]

2-[2-Benzoylamino)benzoylamino]benzoic acid (1) was previously identified as a potent and nontoxic antiadenoviral compound ( Antimicrob. Agents Chemother. 2010 , 54 , 3871 ). Here, the potency of 1 was improved over three generations of compounds. We found that the ortho, ortho substituent pattern and the presence of the carboxylic acid of 1 are favorable for this class of compounds and that the direction of the amide bonds (as in 1) is obligatory. Some variability in the N-terminal moiety was tolerated, but benzamides appear to be preferred. The substituents on the middle and C-terminal rings were varied, resulting in two potent inhibitors, 35g and 35j, with EC(50) = 0.6 μM and low cell toxicity.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2012
Keywords
stem-cell transplantation; immunocompromised host; formazan assay; infection; pcr; recipients; reduction; cidofovir
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-54029 (URN)10.1021/jm201636v (DOI)000302591100027 ()22369233 (PubMedID)2-s2.0-84859800238 (Scopus ID)
Available from: 2012-04-12 Created: 2012-04-12 Last updated: 2023-03-24Bibliographically approved
Gustafsson, D. J., Andersson, E. K., Hu, Y.-L., Marttila, M., Lindman, K., Strand, M., . . . Mei, Y.-F. (2010). Adenovirus 11p downregulates CD46 early in infection. Virology, 405(2), 474-482
Open this publication in new window or tab >>Adenovirus 11p downregulates CD46 early in infection
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2010 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 405, no 2, p. 474-482Article in journal (Refereed) Published
Abstract [en]

Adenovirus 11 prototype (Ad11p), belonging to species B, uses CD46 as an attachment receptor. CD46, a complement regulatory molecule, is expressed on all human nucleated cells. We show here that Ad11p virions downregulate CD46 on the surface of K562 cells as early as 5min p.i. Specific binding to CD46 by the Ad11p fiber knob was required to mediate downregulation. The complement regulatory factors CD55 and CD59 were also reduced to a significant extent as a consequence of Ad11p binding to K562 cells. In contrast, binding of Ad7p did not result in downregulation of CD46 early in infection. Thus, the presumed interaction between Ad7p and CD46 did not have the same consequences as the Ad11p-CD46 interaction, the latter virus (Ad11p) being a promising gene therapy vector candidate. These findings may lead to a better understanding of the pathogenesis of species B adenovirus infections.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-35716 (URN)10.1016/j.virol.2010.06.026 (DOI)000281130500023 ()20638094 (PubMedID)2-s2.0-77955662361 (Scopus ID)
Available from: 2010-09-01 Created: 2010-09-01 Last updated: 2023-03-23Bibliographically approved
Andersson, E. K., Strand, M., Edlund, K., Lindman, K., Enquist, P.-A., Spjut, S., . . . Wadell, G. (2010). Small molecule screening using a whole cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel anti-adenoviral compound. Antimicrobial Agents and Chemotherapy, 54(9), 3871-3877
Open this publication in new window or tab >>Small molecule screening using a whole cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel anti-adenoviral compound
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2010 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, no 9, p. 3871-3877Article in journal (Refereed) Published
Abstract [en]

Adenovirus infections are widespread in society and are occasionally associated with severe, but rarely with life-threatening, disease in otherwise healthy individuals. In contrast, adenovirus infections present a real threat to immunocompromised individuals and can result in disseminated and fatal disease. The number of patients undergoing immunosuppressive therapy for solid organ or hematopoietic stem cell transplantation is steadily increasing, as is the number of AIDS patients, and this makes the problem of adenovirus infections even more urgent to solve. There is no formally approved treatment of adenovirus infections today, and existing antiviral agents evaluated for their anti-adenoviral effect give inconsistent results. We have developed a whole cell-based assay for high-throughput screening of potential anti-adenoviral compounds. The assay is unique in that it is based on a replication competent adenovirus type 11p GFP-expressing vector (RCAd11pGFP). This allows measurement of fluorescence changes as a direct result of RCAd11pGFP genome expression. Using this assay, we have screened 9,800 commercially available small organic compounds. Initially, we observed approximately 400 compounds that inhibited adenovirus expression in vitro by >/= 80% but only 24 were later confirmed as dose-dependent inhibitors of adenovirus. One compound in particular, 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid, turned out to be a potent inhibitor of adenovirus replication.

Place, publisher, year, edition, pages
American society for microbiology, 2010
Keywords
rapid colorimetric assay; adenovirus infection; transplant recipients; in-vitro; immunocompromised host; formazan assay; renal-failure; cidofovir; growth; proliferation
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-35281 (URN)10.1128/AAC.00203-10 (DOI)000281005900048 ()20585112 (PubMedID)2-s2.0-77956097757 (Scopus ID)
Available from: 2010-08-11 Created: 2010-08-11 Last updated: 2023-03-23Bibliographically approved
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