Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation

Wenli Li; Xiuling Li; Tingting Huang; Qihui Teng; Ivana Crnovcic; Christoph Rader; Ben Shen

doi:10.1016/j.bmc.2016.04.017

Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation

Bioorg Med Chem. 2016 Sep 1;24(17):3887-3892. doi: 10.1016/j.bmc.2016.04.017. Epub 2016 Apr 8.

Authors

Wenli Li¹, Xiuling Li², Tingting Huang³, Qihui Teng³, Ivana Crnovcic³, Christoph Rader⁴, Ben Shen⁵

Affiliations

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 Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
⁵ Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI 53705, USA; Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA; Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: [email protected].

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.

Keywords: C-1027; Cancer; Cancer targeting peptide (CTP); Enediyne; Streptomyces globisporus.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aminoglycosides / biosynthesis
Aminoglycosides / pharmacology*
Antineoplastic Agents / pharmacology*
Bacterial Proteins / biosynthesis
Bacterial Proteins / pharmacology*
Cell Line, Tumor
Enediynes / pharmacology*
Feasibility Studies
Fermentation
Humans
Protein Engineering
Streptomyces / metabolism

Substances

Aminoglycosides
Antineoplastic Agents
Bacterial Proteins
Enediynes
C 1027

Grants and funding

R01 CA078747/CA/NCI NIH HHS/United States