Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity

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Model Amphipathic Peptide Coupled with Tacrine to Improve Its Antiproliferative Activity

Segunda, 25.01.2021

Authors and Affiliations:

Sara Silva 1 2 3, Cláudia Alves 4, Diana Duarte 1 2, Ana Costa 5 6, Bruno Sarmento 5 6 7 8, António J Almeida 3, Paula Gomes 4, Nuno Vale 1 9

1 OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal.

2 Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.

3 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003 Lisboa, Portugal.

4 Laboratório Associado para a Química Verde (LAQV), Network of Chemistry and Technology (REQUIMTE), Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal.

5 Instituto de Engenharia Biomédica (INEB), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.

6 Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.

7 Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal.

8 School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Rd, Belfast BT9 7BL, UK.

9 Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.

 

Abstract:

Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group recently reported that Tacrine, used to treat Alzheimer’s Disease, inhibits the growth of breast cancer MCF-7 cells both alone and in combination with a reference drug. In this view, we have now coupled Tacrine with the model amphipathic cell-penetrating peptide (CPP) MAP, to ascertain whether coupling of the CPP might enhance the drug’s antiproliferative properties. To this end, we synthesized MAP through solid-phase peptide synthesis, coupled it with Tacrine, and made a comparative evaluation of the parent drug, peptide, and the conjugate regarding their permeability across the blood-brain barrier (BBB), ability to inhibit acetylcholinesterase (AChE) in vitro, and antiproliferative activity on cancer cells. Both MAP and its Tacrine conjugate were highly toxic to MCF-7 and SH-SY5Y cells. In turn, BBB-permeability studies were inconclusive, and conjugation to the CPP led to a considerable loss of Tacrine function as an AChE inhibitor. Nonetheless, this work reinforces the potential of repurposing Tacrine for cancer and enhances the antiproliferative activity of this drug through its conjugation to a CPP.

 

Journal: International Journal of Molecular Sciences


https://www.mdpi.com/1422-0067/22/1/242