Kuehneromycins A and B, Two New Biological Active Compounds from a Tasmanian Kuehneromyces sp. (Strophariaceae, Basidiomycetes)

1995 ◽  
Vol 50 (1-2) ◽  
pp. 1-10 ◽  
Author(s):  
Gerhard Erkel ◽  
Kirsten Lorenzen ◽  
Timm Anke ◽  
Robert Velten ◽  
Alberto Gimenez ◽  
...  
Keyword(s):  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Dna Polymerases ◽  
Competitive Inhibitor ◽  
Antimicrobial Activities ◽  
Moloney Murine Leukemia Virus ◽  
Strong Inhibitor ◽  
Avian Myeloblastosis Virus ◽  
Reverse Transcriptases ◽  
Murine Leukemia

Abstract In a search for new inhibitors of RNA-directed DNA-polymerases kuehneromycin A (1) was isolated from fermentations of a Tasmanian Kuehneromyces species. Its structure was elucidated by spectroscopic methods. Kuehneromycin A (1) is a non-competitive inhibitor of avian myeloblastosis virus (Ki 200 μᴍ) and moloney murine leukemia virus (Ki 40 μᴍ) reverse transcriptases. The second compound, kuehneromycin B (2) is a strong inhibitor of platelet aggregation stimulated with different inducers. In addition, both compounds exhibit cytotoxic and antimicrobial activities.

Hyphodontal, a New Antifungal Inhibitor of Reverse Transcriptases from Hyphodontia sp. (Corticiaceae, Basidiomycetes)

1994 ◽  
Vol 49 (9-10) ◽  
pp. 561-570 ◽  
Author(s):  
Robert Velten ◽  
Alberto Gimenez ◽  
Wolfgang Steglich
Keyword(s):  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Dna Polymerases ◽  
Competitive Inhibitor ◽  
Moloney Murine Leukemia Virus ◽  
Spectroscopic Methods ◽  
Avian Myeloblastosis Virus ◽  
Antifungal Activities ◽  
Reverse Transcriptases ◽  
Murine Leukemia

Abstract In a search for inhibitors of RNA-directed DNA polymerases a new isolactarane sesquiterpenoid, hyphodontal (1), was isolated from fermentations of a Canadian Hyphodontia species. Its structure was elucidated by spectroscopic methods. Hyphodontal strongly inhibits the growth of several yeasts and is a non-competitive inhibitor of avian myeloblastosis virus (Ki 346 μᴍ) and Moloney murine leukemia virus (Ki 112 μᴍ) reverse transcriptases. In addition, cytotoxic and antifungal activities were observed.

scholarly journals Inhibition of murine leukemia virus with poly-2'-O-(2,4-dinitrophenyl)poly[A].

1996 ◽  
Vol 40 (10) ◽  
pp. 2311-2317 ◽  
Author(s):  
M A Ashun ◽  
Y Hu ◽  
I Kang ◽  
C C Li ◽  
J H Wang
Keyword(s):  
Body Weight ◽  
Murine Leukemia Virus ◽  
Animal Studies ◽  
Leukemia Virus ◽  
Human Lymphocytes ◽  
Antiviral Drug ◽  
Inhibitory Effect ◽  
Moloney Murine Leukemia Virus ◽  
Reverse Transcriptases ◽  
Murine Leukemia

Poly-2'-O-(2,4-dinitrophenyl)poly[A] (DNP-poly[A] is a potent inhibitor of reverse transcriptases from a variety of sources (I. Kang and J. H. Wang, J. Biol. Chem. 269:12024-12031, 1994). In the present study, its inhibitory effect on the reverse transcriptase (RT) from Moloney murine leukemia virus (MuLV) was investigated. DNP-poly[A] was found to enter the virus spontaneously and to completely inhibit the RT within 30 min at 0 degree C. The inhibitor was also spontaneously transported into isolated human lymphocytes and leukocytes at 37 degrees C. Animal studies have demonstrated the effectiveness of DNP-poly[A] as an antiviral drug when administered intraperitoneally at various doses from 1 to 100 mg/kg of body weight. MuLV-infected mice show the presence of RT in their blood as well as increased numbers of leukocytes. After the administration of DNP-poly[A] at a dosage of 100 mg/kg of body weight three times a week over a 3-week period, RT could no longer be detected by an ultrasensitive RT-PCR assay. Autopsy showed that the spleens of infected but untreated mice were enlarged 2- to 10-fold, with fused nodules and the proliferation of large abnormal lymphocytes, whereas the spleens of infected but treated mice resembled the normal spleens of uninfected control mice. These observations indicate that further study of DNP-poly[A] as a general antiretroviral agent is desirable.

Fidelity of two retroviral reverse transcriptases during DNA-dependent DNA synthesis in vitro

1989 ◽  
Vol 9 (2) ◽  
pp. 469-476
Author(s):  
J D Roberts ◽  
B D Preston ◽  
L A Johnston ◽  
A Soni ◽  
L A Loeb ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Leukemia Virus ◽  
Dna Polymerases ◽  
Moloney Murine Leukemia Virus ◽  
Avian Myeloblastosis Virus ◽  
Single Base ◽  
Reverse Transcriptases ◽  
Template Strand ◽  
Cellular Dna

We determined the fidelity of avian myeloblastosis virus and Moloney murine leukemia virus reverse transcriptases (RTs) during DNA synthesis in vitro using the M13mp2 lacZ alpha gene as a mutational target. Both RTs commit an error approximately once for every 30,000 nucleotides polymerized. DNA sequence analysis of mutants generated in a forward mutation assay capable of detecting many types of errors demonstrated that avian myeloblastosis virus RT produced a variety of different mutations. The majority (58%) were single-base substitutions; all of which resulted from the misincorporation of either dAMP or dGMP. Minus-one frameshifts were also common, composing about 30% of the mutations. In addition to single-base events, eight mutants contained sequence changes involving from 2 to 59 bases. The frequency of these mutants suggests that, at least during DNA synthesis in vitro, RTs also commit errors by mechanisms other than classical base miscoding and misalignment. We examined the ability of RTs to synthesize DNA from a mismatched primer terminus at a sequence where the mismatched base was complementary to the next base in the template. Unlike cellular DNA polymerases which polymerize from the mismatched template-primer, RTs preferred to polymerize from a rearranged template-primer containing a matched terminal base pair and an unpaired base in the template strand. The unusual preference for this substrate suggests that the interactions between RTs and the template-primer are different from those of cellular DNA polymerases. The overall error rate of RT in vitro is sufficient to account for the estimated mutation rate of these viruses.

scholarly journals Specific Cleavages by RNase H Facilitate Initiation of Plus-Strand RNA Synthesis by Moloney Murine Leukemia Virus

2003 ◽  
Vol 77 (9) ◽  
pp. 5275-5285 ◽  
Author(s):  
Sharon J. Schultz ◽  
Miaohua Zhang ◽  
James J. Champoux
Keyword(s):  
Dna Synthesis ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Rnase H ◽  
Primer Extension ◽  
Moloney Murine Leukemia Virus ◽  
Cleavage Sites ◽  
Reverse Transcriptases ◽  
Hybrid Substrates ◽  
Murine Leukemia

ABSTRACT Successful generation, extension, and removal of the plus-strand primer is integral to reverse transcription. For Moloney murine leukemia virus, primer removal at the RNA/DNA junction leaves the 3′ terminus of the plus-strand primer abutting the downstream plus-strand DNA, but this 3′ terminus is not efficiently reutilized for another round of extension. The RNase H cleavage to create the plus-strand primer might similarly result in the 3′ terminus of this primer abutting downstream RNA, yet efficient initiation must occur to synthesize the plus-strand DNA. We hypothesized that displacement synthesis, RNase H activity, or both must participate to initiate plus-strand DNA synthesis. Using model hybrid substrates and RNase H-deficient reverse transcriptases, we found that displacement synthesis alone did not efficiently extend the plus-strand primer at a nick with downstream RNA. However, specific cleavage sites for RNase H were identified in the sequence immediately following the 3′ end of the plus-strand primer. During generation of the plus-strand primer, cleavage at these sites generated a gap. When representative gaps separated the 3′ terminus of the plus-strand primer from downstream RNA, primer extension significantly improved. The contribution of RNase H to the initiation of plus-strand DNA synthesis was confirmed by comparing the effects of downstream RNA versus DNA on plus-strand primer extension by wild-type reverse transcriptase. These data suggest a model in which efficient initiation of plus-strand synthesis requires the generation of a gap immediately following the plus-strand primer 3′ terminus.

scholarly journals Fidelity of two retroviral reverse transcriptases during DNA-dependent DNA synthesis in vitro.

1989 ◽  
Vol 9 (2) ◽  
pp. 469-476 ◽  
Author(s):  
J D Roberts ◽  
B D Preston ◽  
L A Johnston ◽  
A Soni ◽  
L A Loeb ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Leukemia Virus ◽  
Dna Polymerases ◽  
Moloney Murine Leukemia Virus ◽  
Avian Myeloblastosis Virus ◽  
Single Base ◽  
Reverse Transcriptases ◽  
Template Strand ◽  
Cellular Dna

We determined the fidelity of avian myeloblastosis virus and Moloney murine leukemia virus reverse transcriptases (RTs) during DNA synthesis in vitro using the M13mp2 lacZ alpha gene as a mutational target. Both RTs commit an error approximately once for every 30,000 nucleotides polymerized. DNA sequence analysis of mutants generated in a forward mutation assay capable of detecting many types of errors demonstrated that avian myeloblastosis virus RT produced a variety of different mutations. The majority (58%) were single-base substitutions; all of which resulted from the misincorporation of either dAMP or dGMP. Minus-one frameshifts were also common, composing about 30% of the mutations. In addition to single-base events, eight mutants contained sequence changes involving from 2 to 59 bases. The frequency of these mutants suggests that, at least during DNA synthesis in vitro, RTs also commit errors by mechanisms other than classical base miscoding and misalignment. We examined the ability of RTs to synthesize DNA from a mismatched primer terminus at a sequence where the mismatched base was complementary to the next base in the template. Unlike cellular DNA polymerases which polymerize from the mismatched template-primer, RTs preferred to polymerize from a rearranged template-primer containing a matched terminal base pair and an unpaired base in the template strand. The unusual preference for this substrate suggests that the interactions between RTs and the template-primer are different from those of cellular DNA polymerases. The overall error rate of RT in vitro is sufficient to account for the estimated mutation rate of these viruses.

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