Biotechnology and Bioprocess Engineering 2024; 29(1): 85-96  
Strategies for the enhancement of anti-cancer effect of phosphodiesterase type 5 inhibitors using drug binding fusion proteins
Hongbin Kim1 · Chang Yeop Keum1 · Su Yeon Lim1 · Kwang Suk Lim1,2
1 Department of Smart Health Science and Technology, Kangwon National University, Chuncheon 24341, Korea
2 Department of Biotechnology and Bioengineering, College of ACE, Kangwon National University, Chuncheon 24341, Korea
Correspondence to: Kwang Suk Lim
kslim@kangwon.ac.kr

Hongbin Kim and Chang Yeop Keum have equally contributed as the first authors to this study.
Received: August 16, 2023; Revised: September 25, 2023; Accepted: September 27, 2023; Published online: February 13, 2024.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Drug repurposing is a rapidly growing for the development of new therapeutic agents. Among them, phosphodiesterase-5 (PDE5) inhibitors, which show excellent effects as a treatment for erectile dysfunction, have been continuously reported for their potential as anti-cancer agents. It is necessary to apply targeted delivery systems to enhance the efficacy of the PDE5 inhibitors (PDE5i) as anti-cancer drugs. In this study, PDE5 inhibitor-binding domain (PBD) was developed to incorporate PDE5i into antibody using biological affinity binding without any chemical modifications. The PBD spontaneously bound with PDE5i, resulting in the formation of PBD/PDE5i complex. We also constructed a recombinant fusion protein composed of an anti-HER2 scFv and PBD (HER2 scFv-PBD) to deliver the PDE5i for the treatment of HER2 positive cancer cells. HER2 scFv-PBD could deliver the PDE5i into HER2-positive cancer cells and enhanced anti-cancer effect of the PDE5i. We have demonstrated the potential of tumor-directed PDE5 inhibition as a novel form of targeted therapy using drug binding fusion proteins.
Keywords: PDE5 inhibitors · Recombinant fusion proteins · Self-assemble · Targeted delivery · HER2


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