Integration of the reverse-transcribed viral DNA into the host genome is an essential step in the lifecycle of retroviruses. Retrovirus integrase (IN) catalyzes insertions of both ends of the linear viral DNA into a host chromosome 1. IN from HIV-1 and closely related retroviruses share the three-domain organization, consisting of a catalytic core domain flanked by N- and C-terminal domains essential for the concerted integration reaction. Although structures of the tetrameric IN-DNA complexes have been reported for IN from prototype foamy virus (PFV) featuring an additional DNA-binding domain and longer interdomain linkers 2–5, the architecture of a canonical three-domain IN bound to DNA remained elusive. Here we report a crystal structure of the three-domain IN from Rous sarcoma virus (RSV) in complex with viral and target DNAs. The structure shows an octameric assembly of IN, in which a pair of IN dimers engage viral DNA ends for catalysis while another pair of non-catalytic IN dimers bridge between the two viral DNA molecules and help capture target DNA. The individual domains of the eight IN molecules play varying roles to hold the complex together, making an extensive network of protein-DNA and protein-protein contacts that show both conserved and distinct features compared to those observed for PFV IN. Our work highlights diversity of retrovirus intasome assembly and provides insights into the mechanisms of integration by HIV-1 and related retroviruses.

Surface fuctionalization plays a crucial role in developing efficient nanoparticulate drug-delivery systems by improving their therapeutic efficacy and minimizing adverse effects. Here we propose a simple layer-by-layer self-assembly technique capable of constructing mesoporous silica nanoparticles (MSNs) into a pH-responsive drug delivery system with enhanced efficacy and biocompatibility. In this system, biocompatible polyelectrolyte multilayers of alginate/chitosan were assembled on MSN's surface to achieve pH-responsive nanocarriers. The functionalized MSNs exhibited improved blood compatibility over the bare MSNs in terms of low hemolytic and cytotoxic activity against human red blood cells. As a proof-of-concept, the anticancer drug doxorubicin (DOX) was loaded into nanocarriers to evaluate their use for the pH-responsive drug release both in vitro and in vivo. The DOX release from nanocarriers was pH dependent, and the release rate was much faster at lower pH than that of at higher pH. The in vitro evaluation on HeLa cells showed that the DOX-loaded nanocarriers provided a sustained intracellular DOX release and a prolonged DOX accumulation in the nucleus, thus resulting in a prolonged therapeutic efficacy. In addition, the pharmacokinetic and biodistribution studies in healthy rats showed that DOX-loaded nanocarriers had longer systemic circulation time and slower plasma elimination rate than free DOX. The histological results also revealed that the nanocarriers had good tissue compatibility. Thus, the biocompatible multilayers functionalized MSNs hold the substantial potential to be further developed as effective and safe drug-delivery carriers.

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BackgroundCoptidis rhizoma (CR) is the dried rhizome of Coptis chinensis Franch., C. deltoidea C. Y. Cheng et Hsiao or C. teeta Wall. (Ranunculaceae) and is commonly used in Traditional Chinese Medicine for the treatment of various diseases including bacillary dysentery, typhoid, tuberculosis, epidemic cerebrospinal meningitis, empyrosis, pertussis, and other illnesses.MethodsA literature survey was conducted via SciFinder, ScieneDirect, PubMed, Springer, and Wiley databases. A total of 139 selected references were classified on the basis of their research scopes, including chemical investigation, quality evaluation and pharmacological studies.ResultsMany types of secondary metabolites including alkaloids, lignans, phenylpropanoids, flavonoids, phenolic compounds, saccharides, and steroids have been isolated from CR. Among them, protoberberine-type alkaloids, such as berberine, palmatine, coptisine, epiberberine, jatrorrhizine, columamine, are the main components of CR. Quantitative determination of these alkaloids is a very important aspect in the quality evaluation of CR. In recent years, with the advances in isolation and detection technologies, many new instruments and methods have been developed for the quantitative and qualitative analysis of the main alkaloids from CR. The quality control of CR has provided safety for pharmacological applications. These quality evaluation methods are also frequently employed to screen the active components from CR. Various investigations have shown that CR and its main alkaloids exhibited many powerful pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetic, neuroprotective, cardioprotective, hypoglycemic, anti-Alzheimer and hepatoprotective activities.ConclusionThis review summarizes the recent phytochemical investigations, quality evaluation methods, the biological studies focusing on CR as well as its main alkaloids.