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Strand, Mårten
Publikationer (8 of 8) Visa alla publikationer
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.
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 1925Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
NATURE PUBLISHING GROUP, 2018
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-144950 (URN)10.1038/s41598-018-20362-9 (DOI)000423663100004 ()29386590 (PubMedID)
Tillgänglig från: 2018-02-22 Skapad: 2018-02-22 Senast uppdaterad: 2018-09-14Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Novel activities of safe-in-human broad-spectrum antiviral agents
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2018 (Engelska)Ingår i: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 154, s. 174-182Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2018
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-150889 (URN)10.1016/j.antiviral.2018.04.016 (DOI)000433651300021 ()29698664 (PubMedID)2-s2.0-85046170096 (Scopus ID)
Tillgänglig från: 2018-08-17 Skapad: 2018-08-17 Senast uppdaterad: 2018-08-17Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria
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2014 (Engelska)Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 12, nr 2, s. 799-821Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
MDPI, 2014
Nyckelord
adenovirus; antiviral; natural products; secondary metabolites; marine actinobacteria; extract screening; butenolides
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
urn:nbn:se:umu:diva-86525 (URN)10.3390/md12020799 (DOI)000335745100011 ()24477283 (PubMedID)
Tillgänglig från: 2014-03-03 Skapad: 2014-02-28 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>The discovery of antiviral compounds targeting adenovirus and herpes simplex virus: assessment of synthetic compounds and natural products
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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. 

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet, 2014. s. 104
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1647
Nyckelord
virology, antiviral, adenovirus, herpes simplex virus, small molecule, inhibitor, hsv, drug discovery
Nationell ämneskategori
Mikrobiologi inom det medicinska området Farmakologi och toxikologi Mikrobiologi
Forskningsämne
medicinsk virologi; datorlingvistik; mikrobiologi
Identifikatorer
urn:nbn:se:umu:diva-88186 (URN)978-91-7601-043-3 (ISBN)
Disputation
2014-05-16, Betula, by 6M, Norrlands universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseVetenskapsrådet, 621-2010-4746Cancerfonden, 100356Vetenskapsrådet, K2007-56X-05688-28-3
Tillgänglig från: 2014-04-25 Skapad: 2014-04-24 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, nr 11, s. 5735-5743Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American Society Microbiology, 2012
Nyckelord
Herpes simplex virus, HSV, inhibitor, 2-[2-(benzoylamino)benzoylamino]benzoic acid, antiviral, Benzavir
Nationell ämneskategori
Infektionsmedicin
Identifikatorer
urn:nbn:se:umu:diva-60354 (URN)10.1128/AAC.01072-12 (DOI)000310055800039 ()22908173 (PubMedID)
Tillgänglig från: 2012-10-09 Skapad: 2012-10-09 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 7, s. 3170-3181Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2012
Nyckelord
stem-cell transplantation; immunocompromised host; formazan assay; infection; pcr; recipients; reduction; cidofovir
Nationell ämneskategori
Kemi
Identifikatorer
urn:nbn:se:umu:diva-54029 (URN)10.1021/jm201636v (DOI)000302591100027 ()22369233 (PubMedID)
Tillgänglig från: 2012-04-12 Skapad: 2012-04-12 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Adenovirus 11p downregulates CD46 early in infection
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2010 (Engelska)Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 405, nr 2, s. 474-482Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-35716 (URN)10.1016/j.virol.2010.06.026 (DOI)000281130500023 ()20638094 (PubMedID)
Tillgänglig från: 2010-09-01 Skapad: 2010-09-01 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, nr 9, s. 3871-3877Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American society for microbiology, 2010
Nyckelord
rapid colorimetric assay; adenovirus infection; transplant recipients; in-vitro; immunocompromised host; formazan assay; renal-failure; cidofovir; growth; proliferation
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-35281 (URN)10.1128/AAC.00203-10 (DOI)000281005900048 ()20585112 (PubMedID)
Tillgänglig från: 2010-08-11 Skapad: 2010-08-11 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
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