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Solution Structure of a Sponge-Derived Cystine Knot Peptide and Its Notable Stability
Li, Huayue,Su, Mingzhi,Hamann, Mark T.,Bowling, John J.,Kim, Hyung Sik,Jung, Jee H. American Chemical Society and American Society of 2014 Journal of natural products Vol.77 No.2
<P>A novel cystine knot peptide, asteropsin E (ASPE), was isolated from an <I>Asteropus</I> sp. marine sponge. The primary, secondary, and tertiary structures of ASPE were determined by high-resolution 2D NMR spectroscopy (900 MHz). With the exception of an <I>N</I>-terminal modification, ASPE shares properties with the previously reported asteropsins A–D, that is, the absence of basic residues, a highly acidic nature, conserved structurally important residues (including two <I>cis</I>-prolines), and a highly conserved tertiary structural framework. ASPE was found to be remarkably stable to gastrointestinal tract enzymes (chymotrypsin, elastase, pepsin, and trypsin) and to human plasma.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jnprdf/2014/jnprdf.2014.77.issue-2/np400899a/production/images/medium/np-2013-00899a_0009.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/np400899a'>ACS Electronic Supporting Info</A></P>
Oh, Joonseok,Liu, Haining,Park, Hyun Bong,Ferreira, Daneel,Jeong, Gil-Saeng,Hamann, Mark T.,Doerksen, Robert J.,Na, MinKyun Elsevier 2017 Biochimica et biophysica acta, General subjects Vol.1861 No.1
<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Inhibition of fatty acid synthase (FAS) is regarded as a sensible therapeutic strategy for the development of optimal anti-cancer agents. Flavonoids exhibit potent anti-neoplastic properties.</P> <P><B>Methods</B></P> <P>The MeOH extract of <I>Sophora flavescens</I> was subjected to chromatographic analyses such as VLC and HPLC for the purification of active flavonoids. The DP4 chemical-shift analysis protocol was employed to investigate the elusive chirality of the lavandulyl moiety of the purified polyphenols. Induced Fit docking protocols and per-residue analyses were utilized to scrutinize structural prerequisites for hampering FAS activity. The FAS-inhibitory activity of the purified flavonoids was assessed via the incorporation of [<SUP>3</SUP>H] acetyl-CoA into palmitate.</P> <P><B>Results</B></P> <P>Six flavonoids, including lavandulyl flavanones, were purified and evaluated for FAS inhibition. The lavandulyl flavanone sophoraflavanone G (<B>2</B>) exhibited the highest potency (IC<SUB>50</SUB> of 6.7±0.2μM), which was more potent than the positive controls. Extensive molecular docking studies revealed the structural requirements for blocking FAS. Per-residue interaction analysis demonstrated that the lavandulyl functional group in the active flavonoids (<B>1</B>–<B>3</B> and <B>5</B>) significantly contributed to increasing their binding affinity towards the target enzyme.</P> <P><B>Conclusion</B></P> <P>This research suggests a basis for the <I>in silico</I> design of a lavandulyl flavonoid-based architecture showing anti-cancer effects via enhancement of the binding potential to FAS.</P> <P><B>General significance</B></P> <P>FAS inhibition by flavonoids and their derivatives may offer significant potential as an approach to lower the risk of various cancer diseases and related fatalities. <I>In silico</I> technologies with available FAS crystal structures may be of significant use in optimizing preliminary leads.</P> <P><B>Highlights</B></P> <P> <UL> <LI> FAS is a pertinent therapeutic target for the development of cancer agents. </LI> <LI> Lavandulyl flavanones exhibited powerful FAS inhibitory activity. </LI> <LI> The lavandulyl functional group contributed to enhancing their binding affinity. </LI> <LI> <I>In silico</I> design and optimization of flavonoid-based FAS inhibitors may be feasible. </LI> </UL> </P>
Significance of endangered and threatened plant natural products in the control of human disease
Ibrahim, Mohamed Ali,Na, MinKyun,Oh, Joonseok,Schinazi, Raymond F.,McBrayer, Tami R.,Whitaker, Tony,Doerksen, Robert J.,Newman, David J.,Zachos, Louis G.,Hamann, Mark T. National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.42
<P>One in five of the world’s plant species is threatened with extinction according to the 2010 first global analysis of extinction risk. Tilman et al. predicted a massive ecological change to terrestrial plants within the next 50–100 y, accompanied by an increase in the number of global plant species facing extinction [Tilman D, et al. (2001) <I>Proc Natl Acad Sci USA</I> 98(10):5433–5440]. Most of the drug-producing plant families contain endangered species never previously studied for their utility to human health, which strongly validates the need to prioritize protection and assessment of these fragile and endangered groups [Zhu F, et al. (2011) <I>Proc Natl Acad Sci USA</I> 108(31):12943–12948]. With little prior attention given to endangered and rare plant species, this report provides strong justification for conservation of the rare plant <I>Diplostephium rhododendroides</I> Hieron., as well as other potential drug-producing endangered species in this and other groups.</P>
Hwang, In Hyun,Oh, Joonseok,Zhou, Wei,Park, Seoyoung,Kim, Joo-Hyun,Chittiboyina, Amar G.,Ferreira, Daneel,Song, Gyu Yong,Oh, Sangtaek,Na, MinKyun,Hamann, Mark T. American Chemical Society and American Society of 2015 Journal of natural products Vol.78 No.3
<P/><P>Colorectal cancer has emerged as a major cause of death in Western countries. Down-regulation of β-catenin expression has been considered a promising approach for cytotoxic drug formulation. Eight 4,9-friedodrimane-type sesquiterpenoids (<B>1</B>–<B>8</B>) were acquired using the oxidative potential of <I>Verongula rigida</I> on bioactive metabolites from two <I>Smenospongia</I> sponges. Compounds <B>3</B> and <B>4</B> contain a 2,2-dimethylbenzo[<I>d</I>]oxazol-6(2<I>H</I>)-one moiety as their substituted heterocyclic residues, which is unprecedented in such types of meroterpenoids. Gauge-invariant atomic orbital NMR chemical shift calculations were employed to investigate stereochemical details with support of the application of advanced statistics such as CP3 and DP4. Compounds <B>2</B> and <B>8</B> and the mixture of <B>3</B> and <B>4</B> suppressed β-catenin response transcription (CRT) via degrading β-catenin and exhibited cytotoxic activity on colon cancer cells, implying that their anti-CRT potential is, at least in part, one of their underlying antineoplastic mechanisms.</P>