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Virus peptide-based pharmaceuticals for the brain

The protective blood-brain barrier (BBB) hampers the delivery of drugs for the treatment of brain cancer, bacterial infections and diseases of the central nervous system. Through innovative drugs derived from viral proteins, INPACT researchers hope to put an end to acquired drug-resistance and deliver pharmaceuticals across the BBB.

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Delivering drugs to the brain is a complex process because of the impermeability of the BBB. The anatomical and functional features of the BBB maintain brain homeostasis and protect it from harmful substances. The BBB prevents drugs from leaving the blood and entering the brain, posing a serious limitation to treating central nervous system diseases, infections and brain tumour metastases. An integrated effort towards novel brain-targeting drugs The EU-funded INPACT was designed to address this issue by developing peptide-based drugs capable of targeting brain tumours and brain-hidden pathogens. The INPACT research, which was undertaken with the support of the Marie Curie programme, brought together academic and industrial partners across the globe. Most conventional drugs target proteins such as enzymes and transporters, but tumours and bacteria can evade their effect through resistance. The rationale was to generate novel pharmaceuticals less prone to drug resistance development. “We aimed at developing stable drugs that could bind to the lipids of membranes of pathogenic bacteria and cancer cells and destroy them,″ explains project coordinator Prof. Miguel Castanho. The consortium included ten members from five countries in four continents with expertise in protein engineering, anticancer drug development and with a portfolio of antibody proprietary technologies. An important aspect of INPACT was its synergistic nature, with different collaborative partners undertaking different tasks and roles to streamline the production of peptide drugs. Having partners with specific expertise in communication, fund raising and business further helped in achieving high impact for INPACT. The project also contributed to the career development of many young researchers who received international and intersectoral training. Exploiting cell-penetrating peptides from viruses for drug design The INPACT approach exploited cell-penetrating peptides (CPPs) from viral proteins using bioinformatics and machine-learning techniques. Various CPPs have been identified that can interact with glycan structures on the surface of cell membranes, carrying therapeutic molecules across cell membranes. Therefore, CPPs play an important role in the development of new therapeutic agents, as the BBB endothelium remains intact. INPACT-generated CPPs from Dengue virus type-2 capsid were further stabilised by peptide engineering and chemically conjugated to small domain antibodies. These chimeric drugs were tested in vitro against immortalised tumour cells and their pharmacokinetic performance was evaluated. Researchers also examined the ability of cyclic antimicrobial peptides to kill or inhibit the growth of bacteria in biofilms. INPACT led to the development of two molecules capable of carrying biological drugs to the brain, and neutralising noxious molecules and pathogens. The technology has been patented and carrier-antibody constructs are now being developed in a biotech pipeline. In addition, antibacterial drug leads have been discovered and are currently being optimised to minimise toxicity. As Prof. Castanho outlines: “The most significant achievement of INPACT was the design of molecules able to shuttle drugs across the BBB.″ With clinical trials planned after the completion of the preclinical tests, the INPACT consortium aims to put their disruptive technologies into clinical practice.

Keywords

INPACT, drug, brain, blood brain barrier (BBB), cell-penetrating peptides (CPPs), virus, pharmaceutical, antibody

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