Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation |
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| Institution: | 1. Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI 53705, USA;2. Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA;3. Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA;4. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA;5. Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL 33458, USA;1. Hematology and Oncology Specialists, LLC, New Orleans, LA;2. Département d''oncologie médicale adulte, Lyon, France;3. Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic;4. Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN;5. Biostatistics and Research Decision Sciences, Asia Pacific MSD R&D (China) Co. Ltd., Beijing, China;6. ARIAD Pharmaceuticals, Inc., Cambridge, MA;7. Merck & Co., Inc., Whitehouse Station, NJ;1. Department of Microbiology, Bharathiar University, Coimbatore-641046, Tamil Nadu, India;2. Department of Microbiology, Periyar University, Salem-636 011, Tamil Nadu, India;1. Istanbul Technical University, Civil Engineering Faculty, Department of Environmental Engineering, 34469 Maslak, Istanbul, Turkey;2. Department of Environmental Health Sciences, University Medical Center Freiburg, Breisacher Strasse 115B, D-79106 Freiburg i.Br, Germany;3. ENVIS Energy and Environmental Systems Research Development Ltd., ITU Ar? Teknokent, Ar? 1 Building, 16, 34469 Maslak, Istanbul, Turkey;1. National University of Science and Technology “MISIS”, Leninsky prospekt 4, Moscow 119049, Russia;2. N.N. Blokhin Russian Cancer Research Center of RAMS, Kashirskoe shosse 24, Moscow 115478, Russia;1. Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, United States;2. School of Environmental and Chemical Engineering, Tianjin Polytechnic University, Tianjin 300387, PR China;1. University of Minnesota, Integrated BioSciences, 1035 University Drive, SMed 223, Duluth, MN 55812-3031, USA;2. University of Minnesota Medical School – Duluth, 1035 University Drive, Duluth, MN 55812-3031, USA;3. Peromyscus Genetic Stock Center University of South Carolina Office of Research, Columbia, SC 29208, USA |
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| Abstract: | Conjugation of cancer targeting peptides (CTPs) with small molecular therapeutics has emerged as a promising strategy to deliver potent (but typically nonspecific) cytotoxic agents selectively to cancer cells. Here we report the engineered production of a CTP (NGR)-containing C-1027 and evaluation of its activity against selected cancer cell lines. C-1027 is an enediyne chromoprotein produced by Streptomyces globisporus, consisting of an apo-protein (CagA) and an enediyne chromophore (C-1027). NGR is a CTP that targets CD13 in tumor vasculature. S. globisporus SB1026, a recombinant strain engineered to encode CagA with the NGR sequence fused at its C-terminus, directly produces the NGR-containing C-1027 that is equally active as the native C-1027. Our results demonstrate the feasibility to produce CTP-containing enediyne chromoproteins by metabolic pathway engineering and microbial fermentation and will inspire efforts to engineer other CTP-containing drug binding proteins for targeted delivery. |
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| Keywords: | Enediyne C-1027 Cancer targeting peptide (CTP) Cancer |
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