"Tandem peptide (pTP-iRGD: CH3(CH)15-GWTLNSAGYLLGKINLKALAALAKKIL-GGK(TAMRA)GGCRGDKGPDC, Cys-Cys bridge) was synthesized by CPC Scientific."
Abstract
Developing new targeted therapy for pancreatic cancer is one of the major current challenges in cancer research. KRAS mutations and miRNA dysregulation (e.g. miR-21-5p oncomiR) play key roles in Pancreatic Ductal Adenocarcinoma (PDAC), leading to rapid progression of the disease. As the KRAS mutation is a main driver of PDAC, anti-KRAS strategies remain a major therapeutic approach for PDAC treatment. Previously, utilization of either siKRAS or small chemically modified single-stranded RNA molecules that specifically disable miR-21 (anti-miR-21) were effective in slowing PDAC tumor growth in various tumor models when packaged in an innovative delivery system (TPN) required for efficient drug delivery to the PDAC tumor site. Here we have tested the utility of targeting the KRAS pathway through multiple mechanisms and via dual targeting of a PDAC oncomiR and oncogene. Initially we found that miR-217, which has been shown to directly regulate KRAS expression, is downregulated in our PDAC samples, thus we tested the benefits of anti-miR-21, miR-217 mimic or siKRAS loaded into the tumor-penetrating nanoparticles (TPN) that we had previously shown to potently target the largely impenetrable PDAC tumors, and found an enhanced anti-tumoral response upon dual treatments in KRAS-mutated PDAC models.
SOCIAL MEDIA
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Diao, J., Komura, R., Sano, T., Pantua, H., Storek, K.M., Inaba, H., Ogawa, H., Noland, C.L., Peng, Y., Gloor, S.L. and Yan, D. bioRxiv (2020): 2020-10.
- Departments of Infectious Diseases, Structural Biology, Biochemical and Cellular Pharmacology, Translational Immunology, Pathology, and Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080 USA
The standard assay consists of 6 μL reaction mixture with 3 nM Lgt-DDM, 50 μM phosphatidylglycerol (1,2-dipalmitoyl-sn-glycero-3-phospho-(1’-rac-glycerol), Avanti), 12.5 μM Pal-IAAC peptide substrate derived from the Pal lipoprotein (MQLNKVLKGLMIALPVMAIAACSSNKN, synthesized by CPC Scientific)
Pantua, H., Skippington, E., Braun, M.G., Noland, C.L., Diao, J., Peng, Y., Gloor, S.L., Yan, D., Kang, J., Katakam, A.K. and Reeder, J. MBio 11, no. 5 (2020): 10-1128.
- Departments of Infectious Diseases, OMNI Bioinformatics, Chemistry, Structural Biology, Biochemical and Cellular Pharmacology, Translational Immunology, Pathology, Molecular Biology, Genentech, South San Francisco, California, USA
MQLNKV-L(U13C6,15N)-KGL(U13C6,15N)MIALPVMAIAA-dipalmitoyl2C-SSNKNGG-K-biotin, which upon cleavage by LspA, yields the product peptide dipalmitoyl2C-SSNKNGG-K-biotin. A product standard [dipalmitoyl2C-SSNKNAAK-(NHCH2CH2NH)-biotin; CPC Scientific] was in the reaction mixture as an internal standard for normalization of product quantitation.
Protein-protein and protein-peptide interactions play critical roles in all types of cellular processing. Peptides are natural partners to proteins and, as ligands, bind to proteins with high affinity due to their capacity to adapt to the often flexible protein surface. Despite this, peptides have drawbacks as drug candidates that include low plasma bioavailability, instability from proteolytic enzymes, and poor passive membrane permeability. Some success has been achieved with linear peptides, particularly peptides that maintain α-helical secondary structures. These motifs can be introduced to stabilized α-helical motifs by common “peptide-stapling” approaches, but stapled peptides can suffer from low bioactivity and poor solubility. Another strategy to maintain peptide secondary structure is modification by macrocyclization.
SAN JOSE, CA., Sept 3, 2020 /CPCNewswire/ — CPC Scientific Inc. is pleased to announce that the European Commission (EC) has granted the Conditional Marketing Authorization (CMA) for MYR Pharmaceuticals lead compound HEPCLUDEX®. CPC Scientific serves as a supplier and partner to MYR Pharmaceuticals for the development and manufacturing of bulevirtide (Hepcludex). This drug is […]
Curreli, Francesca, Sofia MB Victor, Shahad Ahmed, Aleksandra Drelich, Xiaohe Tong, Chien-Te K. Tseng, Christopher D. Hillyer, and Asim K. Debnath. Mbio 11, no. 6 (2020): e02451-20.
We have synthesized (CPC Scientific, Inc.) four stapled peptides, as depicted in Figure 2. We also synthesized the linear peptide, NYBSP-C, as a control. Besides, we purchased a linear peptide, SBP1, to use as a control, which was reported recently to bind to SARS-CoV-2 RBD with high affinity (KD = 47nM).
Abdulganiyyu, I. A.; Kaczmarek, K.; Zabrocki, J.; Nachman, R. J.; Marchal, E.; Schellens, S.; Verlinden, H.; Broeck, J. V.; Marco, H.; Jackson, G. E. Insect Biochemistry and Molecular Biology 2020, 103362.
A head-to-tail cyclic, octapeptide analog of Locmi-AKH-I, cycloAKH (cyclo[LNFTPNWG]) was synthesized to severely restrict the conformational freedom of the AKH structure.
Clairfeuille, T., Buchholz, K.R., Li, Q., Verschueren, E., Liu, P., Sangaraju, D., Park, S., Noland, C.L., Storek, K.M., Nickerson, N.N. and Martin, L. Nature 584, no. 7821 (2020): 479-483.
- Departments of Structural Biology, Infectious Diseases, Microchemistry, Proteomics & Lipidomics, Drug Metabolism & Pharmacokinetics, Translational Immunology, BioMolecular Resources, Biochemical & Cellular Pharmacology, Bioinformatics & Computational Biology, Discovery Chemistry Departments, Genentech Inc., South San Francisco, CA, USA.
LAB peptides ([..], CPC Scientific, [..] l, standard solid-phase peptide synthesis) at 10 mM in 50 mM Tris, pH 8, and 100 mM NaCl were diluted in MHB II cation adjusted broth (800 μM top concentration) or LB. Where indicated, EDTA was added to a final concentration of 0.5 mM.
Chan, Leslie W., Melodi N. Anahtar, Ta-Hsuan Ong, Kelsey E. Hern, Roderick R. Kunz, and Sangeeta N. Bhatia. Nature Nanotechnology (2020): 1-9.
HFA-modifed peptides were synthesized by CPC Scientifc (>95% purity). Briefy, the peptide substrate, Ac-CKKK(Cy5)-PEG4-Nle(O-Bzl)-Met(O)2-Oic-Abu-OH, was synthesized on Fmoc-Abu-CTC resin via standard Fmoc solid phase peptide synthesis.