title: Noncanonical amino acids to improve the pH response of pHLIP insertion at tumor acidity.
abstract: The pH low insertion peptide (pHLIP) offers the potential to deliver drugs selectively to the cytoplasm of cancer cells based on tumor acidosis. The WT pHLIP inserts into membranes with a pH50 of 6.1, while most solid tumors have extracellular pH (pH(e)) of 6.5-7.0. To close this gap, a SAR study was carried out to search for pHLIP variants with improved pH response. Replacing Asp25 with α-aminoadipic acid (Aad) adjusts the pH50 to 6.74, matching average tumor acidity, and replacing Asp14 with γ-carboxyglutamic acid (Gla) increases the sharpness of pH response (transition over 0.5 instead of 1 pH unit). These effects are additive: the Asp14Gla/Asp25Aad double variant shows a pH50 of 6.79, with sharper transition than Asp25Aad. Furthermore, the advantage of the double variant over WT pHLIP in terms of cargo delivery was demonstrated in turn-on fluorescence assays and anti-proliferation studies (using paclitaxel as cargo) in A549 lung cancer cells at pH 6.6.
authors: Department of Chemistry, State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
authors: Joab O
authors: JO
authors: Onyango
authors: Department of Chemistry, State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
authors: Michael S
authors: MS
authors: Chung
authors: Department of Chemistry, State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
authors: Chee-Huat
authors: CH
authors: Eng
authors: Department of Chemistry, State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
authors: Lukas M
authors: LM
authors: Klees
authors: Department of Chemistry, State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
authors: Rachel
authors: R
authors: Langenbacher
authors: Department of Physics, Applied Physics and Astronomy State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
authors: Lan
authors: L
authors: Yao
authors: Department of Chemistry, State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
authors: Ming
authors: M
authors: An
mesh_terms: D015055:1-Carboxyglutamic Acid / Q000737:chemistry; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D015374:Biosensing Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000737:chemistry / Q000633:toxicity; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004337:Drug Carriers; D008565:Membrane Proteins; C533201:pHLIP protein; D015055:1-Carboxyglutamic Acid; D017239:Paclitaxel
keywords: biosensors; cancer; drug delivery; pH low insertion peptide; peptides
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