Papers by Kerry L McPhail
Cell Stress and Chaperones, 2022
Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent... more Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and D-MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure− activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of Nmethyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared.
Molecular networking connects tandem mass spectra of molecules based on the similarity of their f... more Molecular networking connects tandem mass spectra of molecules based on the similarity of their fragmentation patterns. However, during ionization, molecules commonly form multiple ion species with different fragmentation behavior. To connect ion species of the same molecule, we developed Ion Identity Molecular Networking. These new relationships improve network connectivity, are shown to reveal novel ion-ligand complexes, enhance annotation within molecular networks, and facilitate the expansion of spectral libraries.
Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against huma... more Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use it to demonstrate that CbA directly targets the Sec61α subunit of the trimeric Sec61 translocon. CbA binding to Sec61 results in broad substrate-nonselective inhibition of ER protein import and potent cytotoxicity against specific cancer cell lines. CbA targets a lumenal cavity of Sec61α that is partially shared with known Sec61 inhibitors, yet profiling against resistance conferring Sec61α mutations identified from human HCT116 cells suggests a distinct binding mode for CbA. Specifically, despite conferring strong resistance to all previously known Sec61 inhibitors, the Sec61α mutant R66I remains sensitive to CbA. A further unbiased screen for S...
Metabolomics data are difficult to find and reuse, even in public repositories. We, therefore, de... more Metabolomics data are difficult to find and reuse, even in public repositories. We, therefore, developed the Reanalysis of Data User (ReDU) interface (https://redu.ucsd.edu/), a community- and data-driven approach that solves this problem at the repository scale. ReDU enables public data discovery and co- or re-analysis via uniformly formatted, publicly available MS/MS data and metadata in the Global Natural Product Social Molecular Networking Platform (GNPS), consistent with findable, accessible, interoperable, and reusable (FAIR) principles.
Natural product reports, Jan 13, 2018
Covering: up to 2018With contributions from the global natural product (NP) research community, a... more Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.
Journal of applied microbiology, Jan 4, 2018
The current study was conducted to investigate the possible role of a compatible solute from radi... more The current study was conducted to investigate the possible role of a compatible solute from radio-halophilic bacterium against desiccation and ultra-violet radiation induced oxidative stress. Nine different radio-resistant bacteria were isolated from desert soil, where strain WMA-LM19 was chosen for detailed studies on the basis of its high tolerance to ultraviolet radiation among all these isolates. 16S rRNA gene sequencing indicated the bacterium was closely related to Stenotrophomonas sp. (KT008383). A bacterial milking strategy was applied for extraction of intracellular compatible solutes in 70% (v/v) ethanol, which were purified by High Performance Liquid Chromatography (HPLC). The compound was characterized as ectoine by H and C Nuclear Magnetic Resonance (NMR), and Mass Spectrometry (MS). Ectoine inhibited oxidative damage to proteins and lipids in comparison to the standard ascorbic acid. It also demonstrated more efficient preventition (54.80%) against lysis to erythrocyt...
Journal of controlled release : official journal of the Controlled Release Society, 2018
Despite recent advances in the supramolecular assembly of cell-penetrating peptide (CPP) nanostru... more Despite recent advances in the supramolecular assembly of cell-penetrating peptide (CPP) nanostructures, the tuning of size, shape, morphology and packaging of drugs in these materials still remain unexplored. Herein, through sequential ligation of peptide building blocks, we create cell-penetrating self-assembling peptide nanomaterials (CSPNs) with the capability to translocate inside cells. We devised a triblock array of Tat[HIV-1 derived transactivator of transcription] based CPPs, conjugated to up to four Phenylalanine (Phe) residues through an amphiphilic linker, (RADA). We observed that the sequential addition of Phe leads to the transition of CSPN secondary structures from a random coil, to a distorted α-helix, a β-sheet, or a pure α-helix. This transition occurs due to formation of a heptad by virtue of even number of Phe. Atomic force microscopy revealed that CSPNs form distinct shapes reminiscent of a "drill-bit". CSPNs containing two, three or four Phe, self-ass...
mBio, Jan 16, 2018
Secondary metabolites are synthesized by many microorganisms and provide a fitness benefit in the... more Secondary metabolites are synthesized by many microorganisms and provide a fitness benefit in the presence of competitors and predators. Secondary metabolism also can be costly, as it shunts energy and intermediates from primary metabolism. Inspp., secondary metabolism is controlled by the GacS-GacA global regulatory system. Intriguingly, spontaneous mutations inor(Gacmutants) are commonly observed in laboratory cultures. Here we investigated the role of secondary metabolism in the accumulation of Gacmutants instrain Pf-5. Our results showed that secondary metabolism, specifically biosynthesis of the antimicrobial compound pyoluteorin, contributes significantly to the accumulation of Gacmutants. Pyoluteorin biosynthesis, which poses a metabolic burden on the producer cells, but not pyoluteorin itself, leads to the accumulation of the spontaneous mutants. Interspecific competition also influenced the accumulation of the Gacmutants: a reduced proportion of Gacmutants accumulated whenP...
Nature biotechnology, Aug 9, 2016
The potential of the diverse chemistries present in natural products (NP) for biotechnology and m... more The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of…
Journal of Natural Products, 2015
This is an open access article published under an ACS AuthorChoice License, which permits copying... more This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Tetrahedron, 1997
... Printed in Great Britain 00404020 97 17.00 + 0.00 New Spongiane Diterpenes from the East Afri... more ... Printed in Great Britain 00404020 97 17.00 + 0.00 New Spongiane Diterpenes from the East African Nudibranch Chromodoris hamiltoni t Kerry MCPhail and Michael T ... Gonzalez, AG; Estrada, DM; Martin, JD.; Martin, VS.; Perez, C.; Perez, R. Tetrahedron, 1984, 40, 4109. ...
PLoS ONE, 2013
Coibamide A is an N-methyl-stabilized depsipeptide that was isolated from a marine cyanobacterium... more Coibamide A is an N-methyl-stabilized depsipeptide that was isolated from a marine cyanobacterium as part of an International Cooperative Biodiversity Groups (ICBG) program based in Panama. Previous testing of coibamide A in the NCI in vitro 60 cancer cell line panel revealed a potent anti-proliferative response and ''COMPARE-negative'' profile indicative of a unique mechanism of action. We report that coibamide A is a more potent and efficacious cytotoxin than was previously appreciated, inducing concentration-and time-dependent cytotoxicity (EC 50 ,100 nM) in human U87-MG and SF-295 glioblastoma cells and mouse embryonic fibroblasts (MEFs). This activity was lost upon linearization of the molecule, highlighting the importance of the cyclized structure for both anti-proliferative and cytotoxic responses. We show that coibamide A induces autophagosome accumulation in human glioblastoma cell types and MEFs via an mTOR-independent mechanism; no change was observed in the phosphorylation state of ULK1 (Ser-757), p70 S6K1 (Thr-389), S6 ribosomal protein (Ser-235/236) and 4EBP-1 (Thr-37/46). Coibamide A also induces morphologically and biochemically distinct forms of cell death according to cell type. SF-295 glioblastoma cells showed caspase-3 activation and evidence of apoptotic cell death in a pattern that was also seen in wild-type and autophagy-deficient (ATG5-null) MEFs. In contrast, cell death in U87-MG glioblastoma cells was characterized by extensive cytoplasmic vacuolization and lacked clear apoptotic features. Cell death was attenuated, but still triggered, in Apaf-1-null MEFs lacking a functional mitochondria-mediated apoptotic pathway. From the study of ATG5-null MEFs we conclude that a conventional autophagy response is not required for coibamide A-induced cell death, but likely occurs in dying cells in response to treatment. Coibamide A represents a natural product scaffold with potential for the study of mTOR-independent signaling and cell death mechanisms in apoptoticresistant cancer cells.
Phytochemistry Letters, 2013
Phytochemistry, 2010
Two new epimers of malyngamide C, 8-O-acetyl-8-epi-malyngamide C (1) and 8-epi-malyngamide C (3) ... more Two new epimers of malyngamide C, 8-O-acetyl-8-epi-malyngamide C (1) and 8-epi-malyngamide C (3) have been isolated along with known compounds 6-O-acetylmalyngamide F (5), H (6), J (7) K (8), and characterized from a Grenada field collection of the marine cyanobacterium Lyngbya majuscula. The planar structures of these compounds were deduced by 1D-and 2D-NMR and mass spectral data interpretation. The absolute configurations were determined by a combination of CDspectroscopy, chemical degradation and the variable temperature Mosher's method. Compounds 1-5, 7 and 8 displayed moderate cytotoxicity to NCI-H460 human lung tumor and neuro-2a cancer cell lines, with IC 50 values ranging between 0.5 and 20 μg/mL.
Organic Letters, 2012
Four unsaturated polyketide lactone derivatives, coibacins AD , were isolated from a Panamanian m... more Four unsaturated polyketide lactone derivatives, coibacins AD , were isolated from a Panamanian marine cyanobacterium, cf. Oscillatoria sp. The two different types of termini observed in these cooccurring metabolites, either a methyl cyclopropyl ring as seen in curacin A or a methyl vinyl chloride similar to that observed in the jamaicamides, suggest an intriguing flexibility in the "beta branch" forming biosynthetic process. The coibacins possess selective anti-leishmanial activity as well as potent anti-inflammatory activity.
Journal of Natural Products, 1999
... Kerry L. M c Phail, Michael T. Davies-Coleman,* Royston CB Copley, and Drake S. Egglest... more ... Kerry L. M c Phail, Michael T. Davies-Coleman,* Royston CB Copley, and Drake S. Eggleston . Department of Chemistry, Rhodes University, Grahamstown, South Africa, and SmithKline Beecham Pharmaceuticals, Department ...
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Papers by Kerry L McPhail