Precision medicine by designer interference peptides: applications in oncology and molecular therapeutics

Abstract

In molecular cancer therapeutics only 10% of known cancer gene products are targetable with current pharmacological agents. Major oncogenic drivers, such as MYC and KRAS proteins are frequently highly overexpressed or mutated in multiple human malignancies. However, despite their key role in oncogenesis, these proteins are hard to target with traditional small molecule drugs due to their large, featureless protein interfaces and lack of deep pockets. In addition, they are inaccessible to large biologicals, which are unable to cross cell membranes. Designer interference peptides (iPeps) represent emerging pharmacological agents created to block selective interactions between protein partners that are difficult to target with conventional small molecule chemicals or with large biologicals. iPeps have demonstrated successful inhibition of multiple oncogenic drivers with some now entering clinical settings. However, the clinical translation of iPeps has been hampered by certain intrinsic limitations including intracellular localization, targeting tissue specificity and pharmacological potency. Herein, we outline recent advances for the selective inhibition of major cancer oncoproteins via iPep approaches and discuss the development of multimodal peptides to overcome limitations of the first generations of iPeps. Since many protein-protein interfaces are cell-type specific, this approach opens the door to novel programmable, precision medicine tools in cancer research and treatment for selective manipulation and reprogramming of the cancer cell oncoproteome.

Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer

“…However, given the high structural and sequence similarity that exists between Rab proteins and their isoforms, the challenge remains in designing drugs that can specifically target the desired Rab protein without impacting the Rabs required for "house-keeping" functions of the cell. Development of small molecule inhibitors blocking the interactions between Rab and their effectors, [96] could prove a viable approach to enhancing the selectivity of Rab targeting to "edit" the underpinning Rab-signaling network, a strategy that has been successfully exploited with other difficult drugs and highly pleiotropic targets such as C-MYC and RAS proteins [97].…”

From Seabed to Bedside: A Review on Promising Marine Anticancer Compounds

“…Nanoparticle encapsulation is another strategy that has been used to enhance half-life in circulation, solubility in aqueous media and tumor targeting, and to reduce the toxicity and immunogenicity of marine drugs, resulting in increased effectiveness against cancer. Nanoparticles have been successfully used to encapsulate a wide variety of chemotherapeutic drugs and to deliver tumor-targeting components [197][198][199][200]. Nanoparticles have also been deployed to co-deliver marine drugs with other chemotherapeutics to enhance antitumoral activity.…”

“…Changing culture conditions, genetic engineering of organisms [37,178,185] Properly designed and implemented extraction methodologies [179] Structural complexity of the marine compounds In silico screening programs, NMR and MS [75,[185][186][187][188] Correct taxonomic determination Genomic approaches [191][192][193][194] Moderated efficacy Conjugation with antibodies [196] Encapsulation with nanoparticles [201,202] Combination with other drugs [201,202] Use of cell-penetrating peptides and tumor homing peptides [197,199,200,203] High market value Rigorous planning on the usage of marine-derived drugs [162] Another powerful strategy that could enhance the efficacy of marine-derived drugs is the conjugation of marine compounds to cell-penetrating peptides and tumor homing specific peptides such as RGD peptides. Cell-penetrating peptides have the ability to improve the cellular penetrability of therapeutics through the plasmatic and/or nuclear membrane to reach the target, enhancing the efficacy of the marine drug.…”

“…Similarly, the linkage of marine drugs to tumor homing peptides would allow a higher accumulation of the drug in the tumor site, enhancing its anticancer efficacy in a similar way as the antibody of ADCs does. Cell-penetrating peptides and RGD peptides have been extensively used to enhance the anticancer efficacy of therapeutic peptides and other agents [197,199,200,203,204]. However, their applicability in marine drugs has yet to be explored despite the fact that a large number of marine drugs are peptides, peptides derivatives, and small-size molecules.…”

Efficient Development of Platform Cell Lines Using CRISPR-Cas9 and Transcriptomics Analysis

“…While monoclonal antibodies by themselves often have low therapeutic effects, they can be conjugated to highly potent drugs and act as their delivery vehicles totheir target cells marked by specific surface antigens, preventing the drugs from adversely affecting healthy cells (Panowski et al, 2014). Especially promising are peptidic inhibitors that can target specific protein-protein interactions and bring about desired cellular changes, including apoptosis (Sorolla et al, 2020). Antibody drug conjugates (ADCs), as these pairings are known, have been lauded as a revolutionary step in anti-cancer drug development, but successful clinical application has proven challenging and the number of clinically approved systems remains low due to the complicated requirement of optimizing (Peters and Brown, 2015;Tang et al, 2019).…”