Quantitative Evaluation of the Relative Cell Permeability of Peptoids and Peptides

Department of Internal Medicine and Division of Translational Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Journal of the American Chemical Society (Impact Factor: 12.11). 03/2007; 129(6):1508-9. DOI: 10.1021/ja0668623
Source: PubMed


We evaluated quantitatively the relative cell permeability of peptides and peptides using a cell-based reporter gene-based assay. Generally, peptoids were much more cell permeable than the corresponding peptides, though the difference decreased with increasing length. These results suggest that peptoids may be useful reagents for manipulating the activities of intracellular proteins.

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    • "They are particularly suited for the development of peptidomimetic libraries with vast potential for therapeutic application (Patch et al. 2004; Yoo and Kirshenbaum 2008; Fowler and Blackwell 2009; Zuckermann and Kodadek 2009). Peptoids, compared to peptides, have key advantages such as resistance to enzymatic hydrolysis (Simon et al. 1992; Miller et al. 1994) and improved cell permeability (Kwon and Kodadek 2007). Furthermore, peptoids are not immunogenic (Astle et al. 2008) which is vital for the successful development of therapeutics. "
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    ABSTRACT: The solution-phase synthesis and cyclisation of three α,β-peptoid octamers with differing side chain patterns is reported. One of these, compound C, showed a significantly greater resolution by NMR relative to the other two structurally related octamers. This observation was studied in detail by circular dichroism at a synchrotron light source to facilitate the correlation between the side chain patterns and conformational preference of these three peptoids. The X-ray crystal structure of cyclic octamer C, the first high-resolution structure for the α,β-peptoid backbone, was also obtained from methanol. Combined solid- and solution-phase studies allowed the identification of the N-2-(benzyloxy)ethyl side chain on the β-residue of the heterogeneous backbone as a key structural feature driving the increased conformational stability for octamer C.
    Full-text · Article · Apr 2011 · Amino Acids
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    • "For instance, the tumor uptake of 64 Cu-DOTA-VEGF121 in the blockade group only dropped to ~10 %ID/g in U87MG tumors [7], which clearly indicates that 64 Cu-DOTA-VEGF121 lacks VEGFR2 binding specificity . Although 64 Cu-DOTA-GU40C4 showed a relatively low uptake level in PC3 tumors, its steady tumor uptake retention and efficient clearance from non-target organs within the 20 h study period (~2%ID/g) afforded superior tumor imaging contrast, a result that can be attributed to the cell permeable feature of the peptoid conjugate rendered by its positive charge [21] "
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    ABSTRACT: Non-invasive detection of vascular endothelial growth factor receptor 2 (VEGFR2) by positron emission tomography (PET) would allow the evaluation of tumor vascular activity in vivo. Recently, a dimeric peptoid, GU40C4, was reported as a highly potent antagonist of VEGFR2 activation inhibiting angiogenesis and tumor growth in vivo. The purpose of this work was to evaluate the potential of this peptoid for PET imaging of VEGFR2 expression. To label GU40C4 and a control peptoid with a positron emitter, (64)Cu (t(1/2) = 12.7 h; β(+): 0.653 MeV, 17.4%), a cysteine was introduced to the C-terminus of the peptoids and then conjugated to a bifunctional chelator (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) through the maleimide-thiol coupling chemistry. The in vitro binding assay showed a negligible effect of the DOTA conjugation on the VEGFR2 binding affinity of GU40C4. Both peptoid conjugates were efficiently labeled with (64)Cu in high radiochemical yields (> 90%); the specific activity was in the range of 10 - 80 GBq/μmol. PET imaging evaluation using a prostate cancer xenograft (PC3) mouse model showed that (64)Cu-DOTA-GU40C4 had a prominent and steady accumulation in the VEGFR2 positive PC3 tumors (2.25 ± 0.24, 2.15 ± 0.34, and 1.90 ± 0.18 %ID/g at 1, 4, and 20 h p.i., respectively; n = 3), which is significantly higher than the control peptoid conjugate (0.3 - 0.5 %ID/g; p < 0.001 at 1, 4, and 20 h p.i.). Interestingly, the mouse salivary glands were also clearly visualized by (64)Cu-DOTA-GU40C4 (3.17 ± 0.25, 3.00 ± 0.36, and 1.83 ± 0.21 %ID/g at 1, 4, and 20 h p.i., respectively; n = 3) rather than its control peptoid conjugate. VEGFR2 expression in the salivary glands was shown by polymerase chain reaction (PCR) assay. Our results demonstrate that (64)Cu-DOTA-GU40C4 can be used to image the expression of VEGFR2 in vivo.
    Full-text · Article · Jan 2011 · American Journal of Nuclear Medicine and Molecular Imaging
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    • "They are easy to handle and inexpensive to synthesize and optimize. Furthermore, peptoids have high serum-stability [13], are non-immunogenic [34], and are cell permeable [35], thus making them good candidates for use in drug discovery. "
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    ABSTRACT: Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis under physiological and pathological conditions. Anti-VEGF therapy is a clinically proven strategy for the treatment of a variety of cancers including colon, breast, lung, and renal cell carcinoma. Since VEGFR2 is the dominant angiogenic signaling receptor, it has become an important target in the development of novel anti-angiogenic therapies. We have reported previously the development of an antagonistic VEGFR2 peptoid (GU40C4) that has promising anti-angiogenic activity in vitro and in vivo. In the current study, we utilize a derivative of GU40C4, termed GU81 in therapy studies. GU81 was tested alone or in combination with doxorubicin for in vivo efficacy in the MMTV-PyMT transgenic model of breast cancer. The derivative GU81 has increased in vitro efficacy compared to GU40C4. Single agent therapy (doxorubicin or GU81 alone) had no effect on tumor weight, histology, tumor fat content, or tumor growth index. However, GU81 is able to significantly to reduce total vascular area as a single agent. GU81 used in combination with doxorubicin significantly reduced tumor weight and growth index compared to all other treatment groups. Furthermore, treatment with combination therapy significantly arrested tumor progression at the premalignant stage, resulting in increased tumor fat content. Interestingly, treatment with GU81 alone increased tumor-VEGF levels and macrophage infiltration, an effect that was abrogated when used in combination with doxorubicin. This study demonstrates the VEGFR2 antagonist peptoid, GU81, enhances the anti-tumor activity of doxorubicin in spontaneous murine MMTV-PyMT breast tumors.
    Full-text · Article · Jul 2010 · BMC Cancer
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