15 research outputs found
Targeting the Conserved Stem Loop 2 Motif in the SARS-CoV-2 Genome.
RNA structural elements occur in numerous single-stranded positive-sense RNA viruses. The stem-loop 2 motif (s2m) is one such element with an unusually high degree of sequence conservation, being found in the 3' untranslated region (UTR) in the genomes of many astroviruses, some picornaviruses and noroviruses, and a variety of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. The evolutionary conservation and its occurrence in all viral subgenomic transcripts imply a key role for s2m in the viral infection cycle. Our findings indicate that the element, while stably folded, can nonetheless be invaded and remodeled spontaneously by antisense oligonucleotides (ASOs) that initiate pairing in exposed loops and trigger efficient sequence-specific RNA cleavage in reporter assays. ASOs also act to inhibit replication in an astrovirus replicon model system in a sequence-specific, dose-dependent manner and inhibit SARS-CoV-2 replication in cell culture. Our results thus permit us to suggest that the s2m element is readily targeted by ASOs, which show promise as antiviral agents. IMPORTANCE The highly conserved stem-loop 2 motif (s2m) is found in the genomes of many RNA viruses, including SARS-CoV-2. Our findings indicate that the s2m element can be targeted by antisense oligonucleotides. The antiviral potential of this element represents a promising start for further research into targeting conserved elements in RNA viruses.ERC, BBSR
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Long-acting agonists of LH-RH in the treatment of large ovarian endometriomas
Reversible temporary medical oophorectomy using long-acting agonist analogs of LH-RH was tried in three infertile patients suffering from large endometriomas of the ovary. These patients had stage IV disease according to the revised 1985 classification of the American Fertility Society. D-Ala6-des-Gly10-LH-RH propylamide (D-Ala6-LH-RH PA), in a dose of 125 micrograms, was administered intramuscularly every 48 hours to one patient, and daily to the other two patients, for 22, 17, and 14 weeks, respectively. Two patients subsequently received 100 micrograms of D-Trp6-LH-RH for 4 weeks in order to compare its efficacy with D-Ala6-LH-RH PA. Clinical controls, pelvic ultrasonography, and routine laboratory tests and hormone assays were done periodically. Ultrasonography images showed a reduction in the size of endometriomas after the second or third week of treatment. This reduction was maintained throughout and continued after the period of treatment. Suppression of the pituitary and estrogen responses was obtained rapidly, but some transient increments were occasionally found. Progesterone levels always decreased and remained in the range of the early follicular phase. Most intervals of uterine bleeding were prolonged. An evident improvement of abdominal pain, dysmenorrhea, and dyspareunia was found. Administration of D-Trp6-LH-RH was more effective than D-Ala6-LH-RH PA in most of the parameters tested. After discontinuation of treatment, all three patients had a prolonged follicular phase with a normal luteal phase during the first cycle. One woman became pregnant in the fourth cycle after discontinuation of D-Ala6-LH-RH PA and delivered a normal baby.(ABSTRACT TRUNCATED AT 250 WORDS
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Caulobacter crescentus Hfq structure reveals a conserved mechanism of RNA annealing regulation.
We have solved the X-ray crystal structure of the RNA chaperone protein Hfq from the alpha-proteobacterium Caulobacter crescentus to 2.15-Å resolution, resolving the conserved core of the protein and the entire C-terminal domain (CTD). The structure reveals that the CTD of neighboring hexamers pack in crystal contacts, and that the acidic residues at the C-terminal tip of the protein interact with positive residues on the rim of Hfq, as has been recently proposed for a mechanism of modulating RNA binding. De novo computational models predict a similar docking of the acidic tip residues against the core of Hfq. We also show that C. crescentus Hfq has sRNA binding and RNA annealing activities and is capable of facilitating the annealing of certain Escherichia coli sRNA:mRNA pairs in vivo. Finally, we describe how the Hfq CTD and its acidic tip residues provide a mechanism to modulate annealing activity and substrate specificity in various bacteria.SWH and BL are funded by the Wellcome Trust (200873/Z/16/Z). This work was also supported by the NIH (R01 GM120425 to SW, F31 GM123616 to JRJ, and R01 GM078221 to JJG). KF acknowledges funding by the LMU Mentoring program of the LMU Faculty of Biology
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Targeting the Conserved Stem Loop 2 Motif in the SARS-CoV-2 Genome
RNA structural elements occur in numerous single-stranded positive-sense RNA viruses. The stem-loop 2 motif (s2m) is one such element with an unusually high degree of sequence conservation, being found in the 3' untranslated region (UTR) in the genomes of many astroviruses, some picornaviruses and noroviruses, and a variety of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. The evolutionary conservation and its occurrence in all viral subgenomic transcripts imply a key role for s2m in the viral infection cycle. Our findings indicate that the element, while stably folded, can nonetheless be invaded and remodeled spontaneously by antisense oligonucleotides (ASOs) that initiate pairing in exposed loops and trigger efficient sequence-specific RNA cleavage in reporter assays. ASOs also act to inhibit replication in an astrovirus replicon model system in a sequence-specific, dose-dependent manner and inhibit SARS-CoV-2 replication in cell culture. Our results thus permit us to suggest that the s2m element is readily targeted by ASOs, which show promise as antiviral agents. IMPORTANCE The highly conserved stem-loop 2 motif (s2m) is found in the genomes of many RNA viruses, including SARS-CoV-2. Our findings indicate that the s2m element can be targeted by antisense oligonucleotides. The antiviral potential of this element represents a promising start for further research into targeting conserved elements in RNA viruses