61 research outputs found
Exceptional del Pezzo hypersurfaces
We compute global log canonical thresholds of a large class of quasismooth
well-formed del Pezzo weighted hypersurfaces in
. As a corollary we obtain the existence
of orbifold K\"ahler--Einstein metrics on many of them, and classify
exceptional and weakly exceptional quasismooth well-formed del Pezzo weighted
hypersurfaces in .Comment: 149 pages, one reference adde
Alpha-invariants and purely log terminal blow-ups
We prove that the sum of the -invariants of two different Koll\'ar
components of a Kawamata log terminal singularity is less than .Comment: 12 page
Three embeddings of the Klein simple group into the Cremona group of rank three
We study the action of the Klein simple group G consisting of 168 elements on
two rational threefolds: the three-dimensional projective space and a smooth
Fano threefold X of anticanonical degree 22 and index 1. We show that the
Cremona group of rank three has at least three non-conjugate subgroups
isomorphic to G. As a by-product, we prove that X admits a Kahler-Einstein
metric, and we construct a smooth polarized K3 surface of degree 22 with an
action of the group G.Comment: 43 page
QUARTIC DOUBLE SOLIDS WITH ICOSAHEDRAL SYMMETRY
We study quartic double solids admitting icosahedral symmetry.Comment: 19 page
Probing of Exosites Leads to Novel Inhibitor Scaffolds of HCV NS3/4A Proteinase
Hepatitis C is a treatment-resistant disease affecting millions of people worldwide. The hepatitis C virus (HCV) genome is a single-stranded RNA molecule. After infection of the host cell, viral RNA is translated into a polyprotein that is cleaved by host and viral proteinases into functional, structural and non-structural, viral proteins. Cleavage of the polyprotein involves the viral NS3/4A proteinase, a proven drug target. HCV mutates as it replicates and, as a result, multiple emerging quasispecies become rapidly resistant to anti-virals, including NS3/4A inhibitors.To circumvent drug resistance and complement the existing anti-virals, NS3/4A inhibitors, which are additional and distinct from the FDA-approved telaprevir and boceprevir α-ketoamide inhibitors, are required. To test potential new avenues for inhibitor development, we have probed several distinct exosites of NS3/4A which are either outside of or partially overlapping with the active site groove of the proteinase. For this purpose, we employed virtual ligand screening using the 275,000 compound library of the Developmental Therapeutics Program (NCI/NIH) and the X-ray crystal structure of NS3/4A as a ligand source and a target, respectively. As a result, we identified several novel, previously uncharacterized, nanomolar range inhibitory scaffolds, which suppressed of the NS3/4A activity in vitro and replication of a sub-genomic HCV RNA replicon with a luciferase reporter in human hepatocarcinoma cells. The binding sites of these novel inhibitors do not significantly overlap with those of α-ketoamides. As a result, the most common resistant mutations, including V36M, R155K, A156T, D168A and V170A, did not considerably diminish the inhibitory potency of certain novel inhibitor scaffolds we identified.Overall, the further optimization of both the in silico strategy and software platform we developed and lead compounds we identified may lead to advances in novel anti-virals
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