Widely Targeted Metabolomics Analysis of Different Parts of Salsola collina Pall

Salsola collina Pall has a long history of being used as a traditional medicine to treat hypertension, headache, insomnia, constipation and vertigo. However, only a few biologically active substances have been identified from S. collina. Here, the shoots and roots of S. collina, namely L-Sc and R-Sc, were studied. The primary and secondary metabolites were investigated using ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS). A total of 637 putative metabolites were identified and these metabolites were mainly classified into ten different categories. Correlation analysis, hierarchical clustering analysis, principal component analysis and orthogonal partial least squares discriminant analysis of metabolites showed that the L-Sc samples could be clearly separated from the R-Sc samples. Differential accumulated metabolite analysis revealed that most of differential primary metabolites were significantly lower in the L-Sc than in the R-Sc. Conversely, the major differential secondary metabolites had higher levels in the L-Sc than in the R-Sc. Further analysis indicated that the flavonoids were the major putative antioxidant components and most of putative antioxidant components exhibited higher relative concentrations in the L-Sc than the R-Sc. These results improve our understanding of metabolite accumulation and provide a reference for the study of medicinal value in S. collina

Design of cell-permeable nanoneedles as HIV-1 integrase inhibitors

DESIGN OF CELL-PERMEABLE NANONEEDLES AS HIV-1 INTEGRASE INHIBITORS Ya-Qiu Long*,†, Shao-Xu Huang†, ‡, Zahrah Zawahir§,‡, Huiyuan Li†, Tino W. Sanchez§, Ying Zhi†, Frauke Christ¶, Zeger Debyser¶, Nouri Neamati*,§ †State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; §Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033; ¶The Laboratory for Molecular Virology and Gene Therapy, KULeuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium HIV-1 integrase (IN) is an essential enzyme in the viral life cycle and catalyzes the integration of viral DNA into the host genome. It is an attractive therapeutic target for developing HIV-specific drugs because no mammalian counterpart exists for this enzyme. For successful integration of reverse-transcribed viral DNA into the host genome to occur, several interactions with host proteins are required. We have previously demonstrated HIV-1 IN inhibition in vitro with peptides derived from naturally occurring alpha-helical regions of the protein. Two peptides, NL6 and NL9, with low micromolar IC50 values for inhibition of HIV-1 IN catalysis were discovered. Each peptide was derived from the α1 and α3 helical domains of the IN protein, respectively. Alanine scanning on these peptides further pinpointed amino acid residues that were later proven to be critical for IN dimerization and LEDGF/p75-IN interaction. Here we show that hydrocarbon-stapling of these peptides to stabilize their helical structure enables enhanced enzyme inhibitory potency and cell permeability while demonstrating selective inhibition of HIV-1 replication in cell culture. Furthermore, the stabilized peptides demonstrate inhibition of the LEDGF/p75 interaction. The corresponding unstapled peptides do not show inhibition of replication in vivo, although each pair of peptides has similar activity against IN in our in vitro assay. Given their enhanced potency and cell permeability they may serve as prototypical biochemical probes for development into ‘nanoneedles’ for the elucidation of HIV-1 IN and host co-factor interactions within their native cellular environment. To our knowledge this is the first report attempting to design and synthesize stapled-peptides targeting integration events either by directly inhibiting IN or inhibiting its interaction with LEDGF/p75.status: publishe

Design of Cell-Permeable Stapled Peptides as HIV‑1 Integrase Inhibitors

HIV-1 integrase (IN) catalyzes the integration of viral DNA into the host genome, involving several interactions with the viral and cellular proteins. We have previously identified peptide IN inhibitors derived from the α-helical regions along the dimeric interface of HIV-1 IN. Herein, we show that appropriate hydrocarbon stapling of these peptides to stabilize their helical structure remarkably improves the cell permeability, thus allowing inhibition of the HIV-1 replication in cell culture. Furthermore, the stabilized peptides inhibit the interaction of IN with the cellular cofactor LEDGF/p75. Cellular uptake of the stapled peptide was confirmed in four different cell lines using a fluorescein-labeled analogue. Given their enhanced potency and cell permeability, these stapled peptides can serve as not only lead IN inhibitors but also prototypical biochemical probes or “nanoneedles” for the elucidation of HIV-1 IN dimerization and host cofactor interactions within their native cellular environment