Bioscience

SIMM Discovers Novel Tubulin Polymerization Inhibitors

Anti-tubulin agents are widely used in clinic for the therapy of solid tumors. However, the toxicity and intrinsic or acquired resistances limit their clinical efficacy. Therefore, the search for novel anti-tubulin agents with higher efficacy and lower toxicity is of significant importance. Through joint efforts of the research groups led by Lou Liguang and Hu Youhong at the Shanghai Institute of Materia Medica, CAS, a novel series of 2,4,5-substituted pyrimidine derivatives have been designed, synthesized and evaluated for their biological activity. These pyrimidine derivatives inhibit purified tubulin polymerization through binding to tubulin at the colchicine-binding site, induce G2/M cell-cycle arrest and inhibit human tumor cell proliferation. Some indole-pyrimidine compounds may have great potential for further development as anticancer therapeutics. This result was recently reported by the Journal of Medicinal Chemistry (2011, 54：2127-2142).

Basis of Pathogenic Mechanism of Norovirus is Discovered

Noroviruses are a group of small-round structured, non-enveloped RNA viruses causing epidemic acute gastroenteritis in both developing and developed countries. Norovirus possesses an outer protein capsid that encapsulates a single-stranded, positive sense RNA genome. The capsid can be divided into the N-terminal shell (S) and the C-terminal protruding (P) domains, both found to be structurally and functionally independent. The S domain forms the interior shell while the P domain constitutes the arch-like P dimer of the capsid. Functional analyses showed that the P domains could form stable dimers which bind to histo-blood group antigens (HBGAs), the host susceptible factors of noroviruses. The HBGA binding is a prerequisite of norovirus infection and therefore important in the evolution of human noroviruses. Prof. Rao Zihe’s research team at the Institute of Biophysics, CAS recently determined the crystal structures of the P domain protein of the first Lewis-binding norovirus (VA207, GII.9) and revealed the mechanism of its binding specificity in collaboration with Prof. Xi Jiang’s lab at Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center. Co-crystallization of the VA207 P dimer with Ley and sialyl Lex tetrasaccharides showed that VA207 interacts with these antigens through a common site which is highly conserved among most GII noroviruses. However, the HBGA-binding site of VA207 targeted at the Lewis antigens through the α-1, 3 fucose (the Lewis epitope) as major and the β-N-acetyl glucosamine of the precursor as minor interacting sites. These data for the first time elucidate the genetic and structural basis of strain-specificity by a direct comparison of two genetically related noroviruses in their interaction with different HBGAs, highlighting the role of human HBGA as a critical factor in norovirus evolution. The structural data would help antiviral development for disease control and prevention of noroviruses.This achievement was published in the latest issue of PLoS Pathogens (2011, 7(7): e1002152) and titled “Crystallography of a Lewis-Binding Norovirus, Elucidation of Strain-Specificity to the Polymorphic Human Histo-Blood Group Antigens”.

Largest Fungus Found

Recently, Prof. Dai Yu-Cheng of the State Key Laboratory of Forest and Soil Ecology, Institute of Applied Ecology, CAS, and Dr. Cui Baokai of the Beijing Forestry University reported the most massive fruiting body, Fomitiporia ellipsoidea B.K. Cui & Y.C. Dai in the journal Fungal Biology. This fungus belongs to Hymenochaetaceae, Hymenochaetales, Agaricomycetes, Basidiomycota. During the survey on tropical wood-inhabiting fungi in 2010, they found the giant polypore in Hainan Island in southern China. It had a resupinate fruiting body occupying almost the whole underside of a large Cyclobalanopsis patelliformis fallen trunk in a virgin forest and the altitude was 958m. The fruiting body is up to 10m long, 80cm wide and weighs half a ton. The new giant fungus is at least 20 years old, which is reserved at the site for further field observation and microstructure study.