Structure-based design, synthesis, and A-site rRNA cocrystal complexes of functionally novel aminoglycoside antibiotics: C2" ether analogues of paromomycin.

International audienceA series of 2"-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit microM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses

SAR by MS: Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus: Internal Ribosome Entry Site IIA Subdomain

A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' 1 with a KD ∼100 μM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure−activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their KD for the RNA target

Search for the lepton flavor violating τ → 3_μ decay in proton-proton collisions at √s=13 TeV

A search for the lepton flavor violating tau -> 3 mu decay is performed using proton-proton collision events at a center-of-mass energy of 13 TeV collected by the CMS experiment at the LHC in 2017-2018, corresponding to an integrated luminosity of 97.7 fb(-1). Tau leptons produced in both heavy-flavor hadron and W boson decays are exploited in the analysis. No evidence for the decay is observed. The results of this search are combined with an earlier null result based on data collected in 2016 to obtain a total integrated luminosity of 131 fb(-1). The observed (expected) upper limits on the branching fraction.( tau -> 3 mu) at confidence levels of 90 and 95% are 2.9 x 10(-8) (2.4 x 10(-8)) and 3.6 x 10(-8) (3.0 x 10(-8)), respectively.LPHE-L

Search for dark matter particles in W<SUP>+</SUP>W<SUP>-</SUP> events with transverse momentum imbalance in proton-proton collisions at √<i>s</i>=13 TeV

A search for dark matter particles is performed using events with a pair of W bosons and large missing transverse momentum. Candidate events are selected by requiring one or two leptons (l = electrons or muons). The analysis is based on proton-proton collision data collected at a center-of-mass energy of 13TeV by the CMS experiment at the LHC and corresponding to an integrated luminosity of 138 fb(-1). No significant excess over the expected standard model background is observed in the l nu qq and 2l2 nu final states of the W+W- boson pair. Limits are set on dark matter production in the context of a simplified dark Higgs model, with a dark Higgs boson mass above the W+W- mass threshold. The dark matter phase space is probed in the mass range 100-300 GeV, extending the scope of previous searches. Current exclusion limits are improved in the range of dark Higgs masses from 160 to 250 GeV, for a dark matter mass of 200 GeV.LPHE-L