A double-barrel approach

Peptide drug targets two cancer proteins for increased specificity and uptake

May 01, 2021
Kelsey Kaustinen
A double-barrel approach

From left to right, Dr. Law Ga-lai, Prof. Gary Wong Ka-Leung, and Dr. Lung Hong Lok—three of the key researchers on a team that a is working on a dual-targeting drug for cancers linked to the Epstein-Barr virus. CREDIT: Hong Kong Baptist University

HONG KONG—You may expect to find a two-for-one deal at a local shoe store, but probably not at a cancer clinic. Recent work published in Advanced Science may change your mind—researchers from Hong Kong Baptist University (HKBU) developed a dual-targeting drug for cancers linked to the Epstein-Barr virus (EBV). 

This collaborative research was led by Prof. Gary Wong Ka-Leung, head of the Department of Chemistry at HKBU; Dr. Lung Hong Lok, an assistant professor in the same department; and Dr. Law Ga-lai, an associate professor of the Department of Applied Biology and Chemical Technology at The Hong Kong Polytechnic University. Dr. Di Jinming, an associate professor of Surgery of The Third Affiliated Hospital at Sun Yat-sen University, was also part of the research team.

EBV, also known as herpesvirus 4, is one of the most common viruses—nine out of ten people are infected. Although EBV does not cause cancer in most people, it is a culprit in several types of cancer, including nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, and gastric adenocarcinoma.

In this work, the researchers developed a novel drug with a peptide that inhibits two EBV-specific viral proteins key to the development and progression of EBV associated tumors: latent membrane protein 1 (LMP1) and Epstein-Barr nuclear antigen 1 (EBNA1).

As noted in the paper, “LMP1 plays an important role in B cell transformation, proliferation, and survival induced by EBV, induction of epithelial–mesenchymal transition and acquisition of cancer stem cell?like properties, which are subsequently involved in development and progression of EBV?associated tumors.”

The peptide drug is cleaved once it is exposed to the highly acidic tumor microenvironment. The cleaved peptide binds to EBV-infected tumor cells expressing the LMP1 surface protein and invades them where it inhibits the function of EBNA1 in the nucleus. A small dose of 12.5 mg/kg shrunk EBV-positive nasopharyngeal cancer tumors to half their size.

“A synergistic combination of the transmembrane LMP1 targeting ability and the pH responsiveness of UCNP?Pn is found to give specific cancer differentiation with higher cellular uptake and accumulation in EBV?infected cells, thus a lower dose is needed and the side effects and health risks from treatment would be greatly reduced. It also gives responsive UC signal enhancement upon targeted dual?protein binding and shows efficacious EBV cancer inhibition in vitro and in vivo,” the authors stated in the paper.

“The experimental results are good indicators that prove the drug’s efficacy and safety. Since this is the first example of simultaneous imaging and inhibition of two EBV viral proteins, it can serve as a blueprint for a next-generation drug for the safe monitoring and treatment of a specific cancer,” said Wong in a press release.

“Results of this study have demonstrated the successful use of EBV proteins as drug targets, and we envisage our dual?targeting peptide?guided approach could be conveniently translated and applied to other cancers,” the authors concluded.

Work is already underway to pursue this potential new drug. HKBU has established a spinoff company, BP InnoMed Limited (BPI), that will conduct clinical trials for the new drug. BPI was accepted by the Incu-Bio Program of the Hong Kong Science and Technology Park in 2020, where BPI will set up a laboratory for preclinical work on this drug candidate.


Reference

Hong Kong Baptist University https://www.hkbu.edu.hk/eng/main/index.jsp

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