Using porphyrins as albumin-binding molecules to enhance antitumor efficacies and reduce systemic toxicities of antimicrobial peptides

Meiru Song; Ge Liu; Yichang Liu; Ziwei Cheng; Haili Lin; Jianyong Liu; Zaisheng Wu; Jinping Xue; Wanjin Hong; Mingdong Huang; Jinyu Li; Peng Xu

doi:10.1016/j.ejmech.2021.113382

Using porphyrins as albumin-binding molecules to enhance antitumor efficacies and reduce systemic toxicities of antimicrobial peptides

Eur J Med Chem. 2021 May 5:217:113382. doi: 10.1016/j.ejmech.2021.113382. Epub 2021 Mar 15.

Authors

Meiru Song¹, Ge Liu¹, Yichang Liu¹, Ziwei Cheng¹, Haili Lin², Jianyong Liu¹, Zaisheng Wu³, Jinping Xue¹, Wanjin Hong⁴, Mingdong Huang⁵, Jinyu Li⁶, Peng Xu⁷

Affiliations

¹ College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, China; National & Local Joint Biomedical Engineering Research Center on Photodynamic Technologies, Fuzhou University, Fujian, China.
² Department of Pharmacy, The Peoples Hospital of Fujian Province, Fuzhou, China.
³ College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, China.
⁴ Institute of Molecular and Cell Biology, A∗STAR (Agency of Science, Technology and Research), 117608, Singapore.
⁵ College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, China; National & Local Joint Biomedical Engineering Research Center on Photodynamic Technologies, Fuzhou University, Fujian, China; Fujian Key Laboratory of Marine Enzyme Engineering, Fuzhou University, Fuzhou, Fujian 350108, China.
⁶ College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, China; National & Local Joint Biomedical Engineering Research Center on Photodynamic Technologies, Fuzhou University, Fujian, China. Electronic address: j.li@fzu.edu.cn.
⁷ College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350116, China; National & Local Joint Biomedical Engineering Research Center on Photodynamic Technologies, Fuzhou University, Fujian, China; Fujian Key Laboratory of Marine Enzyme Engineering, Fuzhou University, Fuzhou, Fujian 350108, China. Electronic address: pengxu@fzu.edu.cn.

PMID: 33751980
DOI: 10.1016/j.ejmech.2021.113382

Abstract

Antimicrobial peptides (AMPs) are originally developed for anti-infective treatments. Because of their membrane-lytic property, AMPs have been considered as candidates of antitumor agents for a long time. However, their antitumor applications are mainly hampered by fast renal clearance and high systemic toxicities. This study proposes a strategy aiming at addressing these two issues by conjugating AMPs with porphyrins, which bind to albumin increasing AMPs' resistance against renal clearance and thus enhancing their antitumor efficacies. Porphyrins' photodynamic properties can further augment AMPs' antitumor effects. In addition, circulating with albumin ameliorates AMPs' systemic toxicities, i.e. hemolysis and organ dysfunctions. As an example, we conjugated an AMP, K6L9, with pyropheophorbide-a (PPA) leading to a conjugate of PPA-K6L9. PPA-K6L9 bound to albumin with a K_D value at the sub-micromolar range. Combining computational and experimental approaches, we characterized the molecular interaction of PPA-K6L9 with albumin. Furthermore, PPA-conjugation promoted K6L9' antitumor effects by prolonging its in vivo retention time, and reduced the hemolysis and hepatic injuries, which confirmed our design strategy.

Keywords: Albumin; Antimicrobial peptides; Antitumor treatments; Photodynamic effects; Porphyrins; Systemic toxicity.

MeSH terms

Albumins / chemistry*
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Binding Sites
Cell Proliferation / drug effects
Cell Survival / drug effects
Chlorophyll / analogs & derivatives*
Chlorophyll / chemistry
Chlorophyll / pharmacology
Drug Screening Assays, Antitumor
Female
Humans
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / metabolism
Mammary Neoplasms, Experimental / pathology
Mice
Mice, Inbred BALB C
Pore Forming Cytotoxic Proteins / metabolism*
Porphyrins / chemistry
Porphyrins / pharmacology*
Tumor Cells, Cultured

Substances

Albumins
Antineoplastic Agents
Pore Forming Cytotoxic Proteins
Porphyrins
Chlorophyll
pyropheophorbide a