The cytosolic RNA and DNA sensors initiate type I interferon signaling when binding to RNA or DNA. To effectively protect the host against virus infection and concomitantly avoid excessive interferonopathy at resting states, these sensors must be tightly regulated. However, the key molecular mechanisms regulating these sensors' activation remain elusive. Here, we identify PRMT3, a type I protein arginine methyltransferase, as a negative regulator of cytosolic RNA and DNA sensors. PRMT3 interacts with RIG-I, MDA5, and cGAS and catalyzes asymmetric dimethylation of R730 on RIG-I, R822 on MDA5, and R111 on cGAS. These modifications reduce RNA-binding ability of RIG-I and MDA5 as well as DNA-binding ability and oligomerization of cGAS, leading to the inhibition of downstream type I interferon production. Furthermore, mice with loss of one copy of Prmt3 or in vivo treatment of the PRMT3 inhibitor, SGC707, are more resistant to RNA and DNA virus infection. Our findings reveal an essential role of PRMT3 in the regulation of antiviral innate immunity and give insights into the molecular regulation of cytosolic RNA and DNA sensors' activation.

1991-08-01·East African medical journal

Sensitivity of falciparum malaria to chloroquine and amodiaquine in four districts of western Kenya (1985-1987).

Article

作者: Boriga, D A ; Adoyo, A ; Oloo, A J ; Magiri, C ; Koech, D K ; Kariuki, D ; Were, J B

In-vivo and in-vitro studies to determine the sensitivity of Plasmodium falciparum malaria to chloroquine and amodiaquine were conducted in 4 districts of Western Kenya over a 2-year-period. Patients aged 5-60 years, were treated with chloroquine or amodiaquine base 25 mg/kg over 3 days. Recurrence of parasitaemia within 7 days (R1 resistance) or failure to clear parasites (R11 resistance) was observed in 27% of infections in West Pokot district, 51% in Busia, 45% in Bungoma and 19% in Rusinga Island. R111 resistance (failure to decrease parasitaemia by at least 75%) was documented in Rusinga Island. The proportions of parasites with minimum inhibitory concentrations (MICs) for chloroquine greater than 114 nM in in-vitro tests ranged from 37% in Busia to 68% in Bungoma. For amodiaquine, 20% of 30 isolates tested had MICs greater than 80 nM. We conclude that resistance to chloroquine is now established in the area and amodiaquine may be useful in uncomplicated chloroquine resistant falciparum infections in the region.

1989-10-01·Journal of immunology (Baltimore, Md. : 1950)

Polymorphic residues on the I-A beta chain modulate the stimulation of T cell clones specific for the N-terminal peptide of the autoantigen myelin basic protein.

Article

作者: Wraith, D C ; Steinman, L ; Jones, P P ; Davis, C B ; Mitchell, D J ; Todd, J A ; McDevitt, H O ; Zamvil, S S

The effect of polymorphic residues on the A alpha A beta molecule on T cell recognition of the N-terminal nonapeptide of myelin basic protein (R1-9) was determined. Ak-restricted T cell clones recognizing R1-9 were isolated. The peptide-Ia specificities of these clones were determined by testing the response to 1) a panel of peptide analogs of R1-11, 2) splenic APC from mice expressing MHC molecules from serologically distinct haplotypes, and 3) L cell transfectants expressing mutant/recombinant A beta cDNA containing combinations of polymorphic nucleotide sequences from the k and u alleles. Comparisons were made between the Ak-restricted clones and a previously characterized panel of Au-restricted clones. Certain Ak-restricted clones were able to recognize MBP peptide analogs that were not recognized by any of the Au-restricted clones. The Au-restricted T cell clones did not cross-react with R1-9 presented in the context of Ak, whereas the majority of the Ak-restricted clones responded to R1-9 presented in the context of Au. This nonreciprocal cross-reactivity was also reflected in the relative responses of the two sets of T cell clones to the interchange of u- and k-derived residues in the A beta chain. Residues in regions corresponding both the alpha-helical or beta-sheet portions of the hypothetical Ia three-dimensional structure were involved. The results suggest that overall specificity of the T cell clones is the summation of numerous distinct subspecificities for different regions of the peptide-Ia ligand. These results indicate that there can be striking differences in T cell specificity for an autoantigenic epitope, even in the context of A alpha A beta molecules from very closely related haplotypes.

项与 RECCE-111 相关的新闻（医药）

2021-04-01

·BioSpace

Recce Pharmaceuticals Announces Positive Data Against Streptococcus pneumoniae Sinusitis Infection in Animal Model

SYDNEY, Australia, April 01, 2021 (GLOBE NEWSWIRE) -- Recce Pharmaceuticals Ltd (ASX:RCE, FSE:R9Q) (Company), the Company developing New Classes of Synthetic Anti-Infectives, is pleased to announce animal study data showing positive efficacy of a new anti-infective formulation RECCE® 111 (R111) against Streptococcus pneumoniae (S. pneumoniae) bacterial sinusitis in mice. RECCE® 111 is a non-descript title for an experimental compound, developed in-house, building upon the unique mechanisms of action of RECCE® 327. “We’re continually excited by the potential of Recce’s anti-infective compounds and are encouraged by these positive indications,” said James Graham, Chief Executive Officer of Recce Pharmaceuticals. “Moreover, this further enhances the breadth of Recce’s synthetic polymer platform.” The study was conducted by an independent Contract Research Organization, to assess the dose-dependency of R327 and R1111in-vivo antibacterial activity against S. pneumoniae in a mouse model of acute bacterial rhinosinusitis infection. Efficacy of Recce Anti-infectives in Acute Bacterial Rhinosinusitis Treatment Table Group Treatment Clinical Observation 1 Early infection control (day1 post infection) NAD 2 Infection vehicle control, twice daily, oral, 5 days NAD 3 Positive Control (Azithromycin, oral, 200 mg/kg, twice daily, 5 days) NAD 4 RECCE® 327 (Low dose, Nasal, 50 mg/kg, Twice daily, 5 days) NAD 5 RECCE® 327 (Mid dose, Nasal, 100 mg/kg, Twice daily, 5 days) NAD 6 RECCE® 327 (High dose, Nasal, 500 mg/kg, Twice daily, 5 days) NAD 7 RECCE® 327 (Low dose, IV, 100 mg/kg, Twice daily, 5 days) NAD 8 RECCE® 327 (Mid dose, IV, 500 mg/kg, Twice daily, 5 days) NAD 9 RECCE® 327 (High dose, IV, 1000 mg/kg, Twice daily, 5 days) NAD 10 RECCE® 111 (Low dose, IV, 50 mg/kg, Twice daily, 5 days) NAD 11 RECCE® 111 (Mid dose, IV, 100 mg/kg, Twice daily, 5 days) NAD 12 RECCE® 111 (High dose, IV, 250 mg/kg, Twice daily, 5 days) NAD Efficacy Acute Bacterial Rhinosinusitis NAD: No abnormality detected This bacterium was chosen due to its immediate availability as a recognized sinusitis model. Streptococcus pneumoniae, a Gram-positive bacterium, is a leading cause of bacterial pneumonia and meningitis in the United States, and a common cause of bloodstream infections, also known as sepsis, ear and sinus infections.2 A total of 12 groups of 10 mice each were assessed to determine the effectiveness of R327 and R111 against S. pneumoniae. Three groups were treated with varying intranasal doses twice daily of R327 (50, 100, 500 mg/kg) and showed a significant dose-dependent antibacterial effect when compared to early infection and vehicle control (p<0.05). Three groups of mice were treated with varying intravenous doses of R327 (100, 500, 1,000 mg/kg) which showed significant dose-dependent antibacterial effect when compared to early infection control and vehicle control (p<0.05). Furthermore, three groups from the 12 were treated with varying intravenous doses of R111 (50, 100, 250 mg/kg) which showed a significant dose-dependent antibacterial effect when compared to early infection control and vehicle control (p<0.05). Azithromycin was the positive control in the study given twice daily at 200 mg/kg and showed bactericidal effect when compared to vehicle control at five-days post infection (p<0.05). The Company’s R327 and R111 compounds showed significant antibacterial capability with no abnormalities detected and are expected to be subject to further expanded sinusitis studies in due course. In addition to these studies, the Company’s clinical activities with R327 continues to progress in the background and looks forward to updating shareholders in due course. About Recce Pharmaceuticals Ltd Recce Pharmaceuticals Ltd (ASX:RCE, FSE:R9Q) is pioneering the development and commercialisation of New Classes of Synthetic Anti-Infectives designed to address the urgent global health problems of antibiotic resistant superbugs and emerging viral pathogens. Recce’s anti-infective pipeline is unique and comprised of broad-spectrum synthetic polymer antibiotics RECCE® 327, RECCE® 435 and RECCE® 529 for viral infections with unique mechanisms of action against hyper-mutation on bacteria and viruses, respectively. Patented lead candidate RECCE® 327 has been developed for the treatment of blood infections and sepsis derived from E. coli and S. aureus bacteria – including their superbug forms. Recce’s new antibiotic compound, RECCE® 435, has been formulated for oral use. The FDA has awarded RECCE® 327 Qualified Infectious Disease Product designation under the Generating Antibiotic Initiatives Now (GAIN) Act – labelling it for Fast Track Designation, plus 10 years of market exclusivity post approval. Further to this designation, RECCE® 327 has been included on The Pew Charitable Trusts Global New Antibiotics in Development Pipeline as the only synthetic polymer drug candidate for treating sepsis currently in development. Recce wholly owns its automated manufacturing, ready to support first-in-human clinical trials. Recce’s anti-infective pipeline seeks to exploit the unique capabilities of RECCE® technologies targeting synergistic, unmet medical needs. Corporate Contact James Graham Recce Pharmaceuticals Ltd +61 (02) 8075 4585 James.graham@recce.com.au Media and Investor Relations (AU) Andrew Geddes CityPR +61 (02) 9267 4511 ageddes@citypublicrelations.com.au Media and Investor Relations (USA) Meredith Sosulski, Ph.D. LifeSci Communications +1 929 469 3851 msosulski@lifescicomms.com ______________________ 1 ‘R111’ a non-descript placeholder name for present purposes 2 Figures accompanying this announcement are available at: Efficacy of Recce Anti-Infectives in Acute Bacterial Rhinosinusitis Efficacy Acute Bacterial Rhinosinusitis Histology of Sinuses in Acute Bacterial Rhinosinusitis Animal Model Early Infection Control

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