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Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
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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. Vol. 12, nr 2, s. 799-821
Nyckelord [en]
adenovirus; antiviral; natural products; secondary metabolites; marine actinobacteria; extract screening; butenolides
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
URN: urn:nbn:se:umu:diva-86525DOI: 10.3390/md12020799ISI: 000335745100011PubMedID: 24477283OAI: oai:DiVA.org:umu-86525DiVA, id: diva2:699974
Tillgänglig från: 2014-03-03 Skapad: 2014-02-28 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. The discovery of antiviral compounds targeting adenovirus and herpes simplex virus: assessment of synthetic compounds and natural products
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; läkemedelskemi; 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

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Strand, MårtenCarlsson, MarcusUvell, HannaIslam, KoushikulEdlund, KarinCullman, IngerMei, Ya-FangElofsson, MikaelWadell, GöranAlmqvist, Fredrik
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