Happy to share - bit more on AMPs and anti-cancer potential ...
The hurdles listed below (toxicity, distribution) largely overcome by Brilacidin — optimized to be better than natural AMPs.
Intriguing to think about B / HDP-Ms anti-cancer potential, but enough on IPIX plate at moment imo...
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“Tumor cell membrane-targeting cationic antimicrobial peptides: novel insights into mechanisms of action and therapeutic prospects”
Since the discovery of AMPs more than three decades ago, **no other class has matched their versatility as multifunctional compounds.** AMPs have the potential to become the only class that can be used against poly-microbial co-infections (e.g., bacterial and viral) and cancer.
Currently, cancer is a major concern in relation to human mortality, and all types of cancer are characterized by irregular cell growth. Antitumor drugs are subject to differences in target tissue and absorption, which can be particular to each patient. In addition, acquired drug resistance is considered the widespread cause for tumor recurrence.79 At present, some radiolabeled ?-AApeptides have been used as tracers for positron emission tomography, indicating a therapeutic application as anticancer agents.45 In addition, peptidomimetics have been the basis for a number of studies performed to discover new novel anticancer agents.79,80 In this regard, the in vivo inhibitory effects on the growth of tumor cell xenografts in nude mice by the cyclic pentapeptide FC092 ([D-Arg2]-FC131), a CXCR4 antagonist, have been reported.81,82 The intrinsic relationship between its structure and its high specificity to tumor cells is likely playing the key role in the cytotoxicity of peptidomimetics. These characteristics allow the peptidomimetics to bind to cancer cells and disrupt the negatively-charged tumor cell membrane, which is derived from a greater than normal expression of anionic molecules such as sialic acid-rich glycoproteins or phosphatidylserine.83 Importantly, these chemical differences aid the electrostatic interaction of the positively-charged peptide and the negatively-charged tumor cell membranes.80 Studies have reported of AMPs that are effective against bacteria and cancer cells but not against normal mammalian cells such as cecropins from insects and magainins from amphibians.84,85 On the other hand, signal transducer and activator of transcription (STAT) proteins are a family of cytoplasmic transcription factors. Phosphorylation induces their homo- or heterodimerization, and an important function of these dimers is to control gene expression. STAT3 is frequently activated in many human cancer cell lines and is involved in cancer development and progression. Importantly, dysregulation of STAT3 can lead to increase in its activity and contribute to tumorigenesis. Currently, peptidomimetics have been utilized to directly target STAT3 signaling. In this regard, it has been reported that an oxazole-based small-molecule STAT3 inhibitor, which modulates STAT3 stability, induces significant antitumor cellular effects.86 One primary goal of drug delivery for cancer therapy is to increase the amount of drug delivered to the tumor site and decrease its exposure to healthy tissues.87 Recent advances in microencapsulation technologies have been used to enhance drug protectivity, availability, and distribution by employing different biodegradable delivery platforms like liposomes, dendrimers, nanoemulsions, polymeric nanocarriers, and nanoparticles. These nanoformulations can be used to control drug/molecule release and enhance targeted delivery and effectiveness.88 In this regard, Wang and Zhang89 encapsulated a polypeptide isolated from the unicellular green algae Chlorella pyrenoidosa, which exhibited the highest inhibitory activity on human liver HepG2 cancer cells (49%), and they named the polypeptide Chlorella pyrenoidosa antitumor polypeptide. The main mechanism of action of this peptidomimetic is condensation/fragmentation of nuclear chromatin.89 The in vitro release of this peptide against gastric cancer cells provided a basis for the development of encapsulated antitumor peptides. The peptidomimetics KLAKLAKKLAKLAK and the isoAsp-Gly-Arg (or isoDGR) peptides serve as potent tools for developing new antitumor peptides. They can selectively kill CD13-/avß3+ breast cancer cells in both in vitro and in vivo experiments by inhibiting angiogenesis by binding to avß3+, which is increased on tumor cells.90 Currently, the antitumor role of the analgesic-antitumor peptide (AGAP) isolated from the scorpion Buthus martensii has been reported. This protein, consisting of a small ubiquitin-related modifier linked with a hexahistidine tag from E. coli, was used as an antitumor peptide, and the main mechanism of action of this peptidomimetic is through cell cycle arrest.91 The recombinant system AGAP showed considerable inhibition of lymphoma and glioma propagation.91 Interestingly, using SW480 human colon cancer cells, it was proposed that recombinant AGAP induces cell cycle arrest in the G0/G1 phase, attended by the decrease in the S phase without significant change in the G2/M phase.91 Together, these studies strongly suggest that the use of peptidomimetics is a potent tool for developing new antitumor peptides. The main limitations in the use of these peptides are their poor bioavailability due to insolubility related to their intrinsic physicochemical properties, potential toxicity to host cells, tissue distribution, and poor pharmacokinetic issues. Despite these disadvantages, antitumor peptidomimetics have potential due to their high potency and specificity against malignant cells.
It is important to consider that further studies are needed to investigate the cost of large scale production of peptidomimetics and the transition of these peptides from the laboratory to the clinic to confirm that they provide an effective new class of therapeutic agents. However, the combination of the therapeutic use of peptidomimetics and conventional therapy against cancer (eg, chemotherapy, radiotherapy, or surgical procedures) can help in overcoming drug resistance in cancer cells. Increased funding and innovative research approaches to prepare peptidomimetics are required for practical use of these peptides as therapeutic agents.
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