Applications of Cyclic Peptides in Pharmaceuticals
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History of Cyclic Peptides in Pharmaceuticals
Cyclic peptides, although recently discovered in scientific terms, have roots deeply embedded in the traditional medicine practices of various indigenous communities, particularly in Africa. Historically, cyclic peptide-containing plants like Oldenlandia affinis were revered for their medicinal properties and were integral to the healing rituals and remedies of these communities. Among the Bantu-speaking tribes of Central and Southern Africa, cyclic peptide-rich plants were commonly used for childbirth assistance, treating wounds, and alleviating various ailments.
Traditional healers, or shamans, possessed extensive knowledge of the properties and applications of cyclic peptide-containing plants which made the utilization of cyclic peptides in traditional medicine not merely anecdotal but deeply rooted in indigenous knowledge systems passed down through generations. They developed intricate methods of preparation and administration to extract the therapeutic benefits while minimizing adverse effects. These practices were often steeped in ritual and cultural significance, highlighting the reverence and respect accorded to these natural remedies.
The transition of cyclic peptides from traditional medicine to modern pharmaceuticals began with their discovery and characterization by scientists in the 1990s. Initially isolated from Oldenlandia affinis, cyclic peptides were recognized for their unique cyclic structure, which imparted exceptional stability and resistance to enzymatic degradation. This discovery sparked interest among researchers, leading to extensive studies on cyclic peptides' biological activities and potential pharmaceutical applications.
The integration of cyclic peptides into contemporary medicine represents a convergence of traditional wisdom and modern scientific inquiry. While traditional uses laid the foundation for recognizing the therapeutic potential of cyclic peptides, advancements in biotechnology and pharmacology have enabled their exploration in various medical contexts. Today, cyclic peptides are studied in numerous fields, not just for their antimicrobial, anticancer, and immunomodulatory properties but also as potential drug delivery vehicles and novel therapeutic agents in the treatment of diverse diseases.
Structure of cyclic peptides used in clinic.
Left top: Tyrocidine A, cyclo (Val-Orn-Leu-D-Phe-Pro-Phe-Phe-Asn-Gln-Tyr).
Left bottom: Gramicidin S, cyclo (Val-Orn-Leu-D-Phe-Pro)2.
Right: Cyclo-RGD Peptide EMD 66203, cyclo (Arg-Gly-Asp-D-Phe-Val). (Sang Hoon Joo)
Cyclic Peptides Mechanism of Action
The unique cyclic cystine knot (CCK) motif makes cyclic peptides hold diverse biological activities and structural stability which help them possess remarkable potential for pharmaceutical applications. This stability is a result of the cyclic backbone formed by disulfide bonds, rendering cyclic peptides highly resistant to proteolytic degradation and extreme environmental conditions. Such robustness makes them promising candidates for various therapeutic interventions. Cyclic peptides' interactions with cellular membranes and intracellular targets lead to their biological activities. One of the primary mechanisms of action involves their ability to selectively disrupt lipid bilayers, a process facilitated by their amphipathic nature. The hydrophobic and cationic regions of cyclic peptides can penetrate cell membranes and insert themselves into lipid bilayers, leading to membrane destabilization and subsequent cell lysis. This mechanism underlies their potent antimicrobial activity against bacteria, fungi, and other pathogens.
Additionally, cyclic peptides exhibit selective targeting of cancer cells, primarily through interactions with membrane-associated proteins or receptors overexpressed in malignant cells. Cyclic peptides bind to these targets to induce apoptosis or disrupt vital cellular processes, thereby inhibiting tumor growth and metastasis. Their ability to specifically target cancer cells while sparing healthy tissues holds immense promise for developing safer and more effective anticancer therapies.
Cyclic peptides modulate their immunomodulatory properties to realize immune responses and inflammation which also can be used to treat autoimmune diseases or prevent organ rejection in transplant recipients. They regulate immune cell function and cytokine production. That offers potential therapeutic avenues to manage immune-related disorders.
Advantages and Disadvantages of Cyclic Peptides
The cystine knot motif of cyclic peptides can provide resistance to thermal, chemical, and enzymatic degradation. Due to it and the cyclic structure, cyclic peptides hold several advantages, including exceptional stability. Cyclic peptides exhibit high biological activity at low concentrations. Therefore, they can translate to lower dosages and reduce side effects in therapeutic applications. Additionally, they are versatile tools to be used in various pharmaceutical applications, from antimicrobial agents to anticancer therapies and drug delivery systems because of their diverse biological activities and potential for modification.
There are significant concessions. However, due to the intricate structure of cyclic peptides, great efforts have been required to advance recombinant DNA technology and synthetic biology, which provided significant obstacles to large-scale synthesis and production. To achieve selectivity and safety of cyclic peptides in therapeutic applications, characterization of their cell-specificity and cytotoxicity and modifications might be required. Deliverability and bioavailability of cyclic peptides in the human body are also hurdles that need to be circumvented with creative delivery systems and formulation strategies to extract the most of their therapeutic potential.
Cyclic Peptides at Creative Peptides
Application of Cyclic Peptides in Pharmaceuticals
Cyclic peptides attracted significant interest for their potential applications in pharmaceuticals as a result of their remarkable stability and diverse biological activities. In this context, cyclic peptides serve as novel therapeutic agents for addressing a wide range of medical conditions, from antimicrobial and anticancer treatments to immunomodulatory therapies.
Many studies showed cyclic peptides combating bacterial and fungal infections due to their potent antimicrobial activity. Research has shown that cyclic peptides exhibit broad-spectrum efficacy against a wide range of pathogens, including antibiotic-resistant strains. Importantly, cyclic peptides are valuable assets in the fight against growing antimicrobial resistance by minimizing the likelihood of developing resistance.
Conventional antibiotics are notoriously difficult to eradicate biofilm-forming pathogens but cyclic peptides have shown efficacy against them in various studies. Biofilms are highly resistant to antimicrobial agents due to their complex microbial communities encased in a protective matrix. However, cyclic peptides offer a promising approach to combating biofilm-associated infections by penetrating biofilms and disrupting microbial membranes.
In addition, resistance to degradation in different physiological conditions makes them attractive molecules as antimicrobial agents. Conventional antibiotics may degrade rapidly or lose efficacy in harsh environments, however, cyclic peptides retain their activity even under adverse conditions. This stability, coupled with their potent antimicrobial properties, positions cyclic peptides as attractive candidates for the development of next-generation antibiotics capable of addressing the urgent threat of antimicrobial resistance.
Cyclic peptides have garnered attention for their ability to selectively target cancer cells while sparing healthy tissues, a crucial advantage over conventional chemotherapy.
Traditional chemotherapeutic agents often cause collateral damage to healthy cells because they lack specificity. However, the mode of action and unique structural features of cyclic peptides help them recognize and bind to cancer cell membranes with high affinity to discriminate between cancerous and non-cancerous cells which is different from traditional chemotherapeutic agents. Once bound to cancer cell membranes, cyclic peptides exert their cytotoxic effects through various mechanisms, including membrane disruption, induction of apoptosis, and interference with intracellular signaling pathways essential for tumor growth and survival. By disrupting cancer cell membranes, cyclic peptides can compromise cell integrity, leading to cell death while minimizing damage to surrounding healthy tissues. This targeted approach holds promise for developing safer and more effective anticancer therapies with reduced side effects and improved patient outcomes.
Besides, cyclic peptides offer advantages in terms of stability and bioavailability, crucial factors for successful cancer treatment. Their cyclic structure confers exceptional stability, enabling them to withstand enzymatic degradation and harsh physiological conditions encountered in the body. In addition, cyclic peptides' pharmacokinetic properties can be enhanced by engineered or modified, researchers can prolong cyclic peptide circulation time or improve tissue penetration to further optimize their efficacy as anticancer agents.
Overall, cyclic peptides are a class of anticancer agents with the potential to revolutionize the cancer treatment paradigm. They develop targeted therapy to reduce side effects and improve the prognosis of patients with valuable drug candidates by selectively targeting and destroying cancer cell membranes, coupled with their stability and bioavailability. Continued research and innovation in cyclic peptide-based anticancer therapies hold great promise for advancing the field of oncology and improving the lives of patients with cancer.
Drug Delivery Systems
The cyclic structure and disulfide bonds of cyclic peptides ensure exceptional stability which means they can be applied for drug delivery. Their resistance to enzymatic degradation and harsh physiological conditions ensures the integrity of both the carrier molecule and the payload, minimizing premature drug degradation and maximizing therapeutic efficacy. This stability is particularly advantageous for delivering sensitive or labile drugs that would otherwise degrade rapidly in vivo.
Cyclic peptides' structural features, including their compact size and well-defined three-dimensional structure, facilitate efficient drug encapsulation and delivery. The cyclic cystine knot (CCK) motif provides a rigid scaffold for attaching or encapsulating therapeutic agents, ensuring their stability during transport and release. Cyclic peptides can be engineered or modified to incorporate various payloads, ranging from small molecules to peptides or nucleic acids, thereby expanding their versatility as drug carriers.
Furthermore, cyclic peptides' ability to penetrate cellular membranes enhances drug delivery to target cells or tissues. The amphipathic nature of cyclic peptides allows them to interact with lipid bilayers and facilitate cellular uptake, promoting intracellular delivery of encapsulated drugs. This targeted delivery approach reduces systemic exposure and off-target effects, minimizing adverse reactions and improving the therapeutic index of the encapsulated drugs.
Immunosuppressive Therapies
Cyclic peptides can modulate immune responses, making them attractive candidates for treating autoimmune diseases characterized by dysregulated immune activity. By selectively targeting key components of the immune system, cyclic peptides can attenuate excessive inflammation and suppress aberrant immune responses underlying autoimmune conditions. This immunomodulatory effect holds the potential for alleviating symptoms and slowing disease progression in patients with autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and lupus.
Cyclic peptides' immunosuppressive properties are particularly relevant in the context of organ transplantation, where preventing graft rejection is paramount. Transplanted organs are susceptible to rejection by the recipient's immune system, necessitating lifelong immunosuppressive therapy to maintain graft viability. Cyclic peptides offer a novel approach to immunosuppression by selectively targeting immune cells involved in graft rejection, such as T cells and antigen-presenting cells. By modulating immune responses at the site of transplantation, cyclic peptides hold promise for improving graft acceptance and long-term transplant outcomes while minimizing the risk of systemic side effects associated with conventional immunosuppressive agents.
Cyclic peptides' ability to modulate immune responses without compromising overall immune function is a significant advantage in immunotherapy. Unlike traditional immunosuppressive drugs, which globally suppress immune activity and increase susceptibility to infections, cyclic peptides can selectively target pathological immune responses while preserving protective immunity against pathogens. This selective immunomodulation offers a more nuanced approach to managing immune-related disorders, balancing therapeutic efficacy with minimal impact on host defense mechanisms.
Conclusion
Cyclic peptides are used in traditional medicine to modern scientific exploration and represent a promising frontier in pharmaceutical development. Their remarkable properties and diverse applications make them valuable assets in addressing complex medical challenges. With ongoing advancements, cyclic peptides are poised to make significant contributions to the future of medicine.
References
- Joo S H. Cyclic peptides as therapeutic agents and biochemical tools[J]. Biomolecules & therapeutics, 2012, 20(1): 19.
- Zorzi A, Deyle K, Heinis C. Cyclic peptide therapeutics: past, present and future[J]. Current opinion in chemical biology, 2017, 38: 24-29.
- Ojeda P G, Cardoso M H, Franco O L. Pharmaceutical applications of cyclotides[J]. Drug Discovery Today, 2019, 24(11): 2152-2161.
