What are peptides and their uses in medical therapy?

Peptides in Medical Therapy

What Are Peptides?

Peptides are short chains of amino acids (typically 2-50 amino acids) linked by peptide bonds that serve as fundamental signaling molecules throughout biological systems and have emerged as a distinct therapeutic class between small molecules and larger proteins. 1

Peptides differ from proteins primarily by size and structure—oligopeptides contain fewer than 10-20 amino acids, polypeptides contain more than 20 amino acids, while proteins typically comprise more than 50 amino acids and often contain multiple peptide subunits. 2

Current Therapeutic Applications

Established Medical Uses

• More than 80 peptide-based drugs have reached the market for conditions including diabetes, cardiovascular diseases, and urological disorders, with over 150 additional peptides currently in clinical development. 1

• Peptides function as hormone analogs, enzyme modulators, toxins, antibiotics, and signaling molecules that regulate fundamental physiological processes. 2, 3

• The first commercial peptide drug, insulin, initiated peptide therapeutics in the 1920s, establishing a century-long foundation for peptide-based medicine. 3

Cardiovascular Applications: Natriuretic Peptides

• B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) serve as quantitative biomarkers for cardiac stress and heart failure, with BNP >400 pg/mL providing strong diagnostic confirmation (positive likelihood ratio >10). 4

• Natriuretic peptides promote natriuresis, diuresis, vasodilation, and antagonize the renin-angiotensin-aldosterone and sympathetic nervous systems while modulating myocardial and vascular structure through anti-proliferative and cytoprotective effects. 4

• These peptides are secreted from cardiac myocytes in response to pressure or volume overload, with ventricular myocytes re-expressing fetal genes including ANP and BNP during cardiac pathologies. 4

• BNP levels <100 pg/mL effectively exclude acute heart failure with 90% sensitivity and 94% negative predictive value, while levels >400 pg/mL strongly indicate heart failure. 4

Oncology Applications: Synthetic Peptide Vaccines

• Synthetic long peptides (SLPs) of 15-30 amino acids containing core predicted neoantigens represent an effective delivery mechanism in personalized cancer immunotherapy, demonstrating superior efficacy compared to short synthetic peptides of 8-11 amino acids. 4

• SLPs require internalization and processing by professional antigen-presenting cells (APCs), whereas short peptides can induce immunological tolerance by binding directly to MHC-I on non-professional APCs. 4

• Multiple delivery mechanisms exist for neoantigen vaccines including synthetic peptides, DNA, mRNA, viral vectors, and ex-vivo-loaded dendritic cell vaccines. 4

Neuroendocrine Tumor Treatment: Radiolabeled Peptides

• Radiolabeled peptides (DOTATOC, DOTATATE, DOTA-lanreotide, DOTANOC) with Yttrium-90 or Lutetium-177 achieve objective response rates of 9-33% in neuroendocrine tumors, with median time to progression of 29 months and overall survival of 36.7 months. 4

• Activities of 3-6 GBq administered at 6-8 week intervals to cumulative activities of 12-18 GBq are recommended, with most patients reporting subjective benefit within two treatment cycles. 4

• Main toxicities include temporary myelosuppression and radiation nephritis, with co-administration of amino acids (particularly D-lysine) essential to minimize renal toxicity by reducing tubular peptide binding. 4

Growth Hormone Therapy: Somatropin

• Somatropin binds to dimeric GH receptors in cell membranes, triggering intracellular signal transduction that stimulates linear growth primarily through IGF-1 production in the liver and locally in tissues. 5

• The peptide increases incorporation of sulfate into proteoglycans in cartilaginous growth areas of long bones, mediated by somatomedins or insulin-like growth factors rather than direct effects. 5

• Somatropin increases total skeletal muscle cell number and size, influences internal organ size, increases red cell mass, and stimulates intracellular lipolysis leading to increased plasma free fatty acids and triglycerides. 5

• Following subcutaneous injection of 5 mg, peak concentration (Cmax) reaches 72-74 mcg/L at 4.0 hours, with mean terminal half-life of 2.5 hours and metabolism occurring in liver and kidneys by proteolytic degradation. 5

Advanced Drug Delivery Applications

Targeted Drug Delivery

• Peptides enable targeted drug delivery to specific cell types (cancer cells, immune cells) by conjugating drugs to carrier peptides that recognize receptors with higher expression on target cells, thereby lowering side effects by sparing normal cells. 6

• Peptides derived from intercellular junction proteins (occludins, claudins, cadherins) improve drug delivery through the intestinal mucosa barrier (IMB) and blood-brain barrier (BBB) via paracellular pathways. 6

• These modulator peptides hypothetically increase porosity of paracellular pathways by modulating protein-protein interactions in intercellular junctions, enhancing brain delivery of small molecules, medium-sized peptides, and large proteins up to 65 kDa albumin. 6

Biomarker Applications in Cardio-Oncology

• High-sensitivity cardiac troponin I elevation with decreased global longitudinal strain (GLS) of at least 19% is highly specific in predicting chemotherapy-induced myocardial injury in patients receiving anthracycline or trastuzumab. 4

• Persistent elevation of BNP following anthracycline treatment indicates adverse cardiac outcomes, with transient increases typically not predictive of clinical outcomes unless elevation persists. 4

• BNP increase during anthracycline treatment correlates with E/A ratio increase, suggesting predictive value for diastolic dysfunction, though significant correlations with natriuretic peptides typically emerge only after cumulative doxorubicin doses reach 500 mg/m². 4

Cosmetic and Dermatologic Applications

• Peptides improve photodamaged skin by increasing dermal thickness, promoting neocollagenosis, enhancing collagen organization, and increasing fibroblast activity. 7

• Relaxin peptides inhibit collagen biosynthesis and promote collagen breakdown by acting directly on transforming growth factor-β-stimulated human dermal fibroblasts to decrease type I and III collagen synthesis while increasing matrix metalloproteinase expression. 7

• Platelet-Rich Fibrin (PRF) containing natural growth factors and peptides shows promising results for periorbital rejuvenation, improving periocular wrinkles, hyperpigmentation, and skin thickness. 7

Structural and Functional Characteristics

• Peptides occupy unique chemical space between small molecules and larger proteins, with structures including linear chains, cycles, post-translational modifications, unusual amino acids, and stabilizing motifs. 1

• They function as intrinsic signaling molecules (neuropeptides, peptide hormones), toxins for prey capture, and defense molecules against enemies and microorganisms. 1

• Peptides carry fundamental molecular information for biological processes and interfere with protein-protein interactions that are indispensable in bio-processes. 3

Clinical Pitfalls and Considerations

Natriuretic Peptide Interpretation

• Obesity significantly reduces natriuretic peptide levels through increased clearance and suppression of pro-BNP synthesis, potentially masking underlying cardiac dysfunction despite significant disease. 8

• Atrial fibrillation increases BNP and NT-proBNP concentrations even without heart failure, requiring higher diagnostic cutoff values in this population. 8

• Renal dysfunction elevates NT-proBNP independent of cardiac function, with severe renal failure (GFR <30 mL/min/1.73 m²) producing extremely high levels driven more by decreased clearance than heart failure severity alone. 4, 8

• Patients on sacubitril/valsartan (ARNI) show increased BNP levels because BNP is a substrate for neprilysin, but NT-proBNP levels remain unaffected—therefore only NT-proBNP should be used for monitoring patients on ARNI therapy. 8

Peptide Manufacturing Challenges

• Certain chemical properties of amino acid sequences make peptides difficult to synthesize, with longer peptides encountering solubility problems (becoming insoluble). 4

• Manufacturability prediction incorporates nine properties contributing to synthesis difficulty, including hydrophobic sequences, cysteine residues, and asparagine-proline bonds. 4

• For DNA vector delivery, effective junctions and spacers must be designed to ensure correct proteasomal cleavage and avoid inadvertent immunogenic junction antigens. 4

Future Directions

• Peptidomics—the comprehensive qualitative and quantitative analysis of peptides in biological samples—employs techniques from genomics, modern proteomics, state-of-the-art analytical chemistry, and innovative computational biology for peptide discovery and characterization. 1

• Peptides are gaining popularity as biomarkers and innovative therapeutics, with their receptor selectivity and ability to cross membranes or reach intracellular targets offering advantages that can hardly be mimicked by other chemical substances. 6, 3

• Advanced nano-supramolecular technologies, aptamers, altered peptide ligands, in silico methodologies, smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems represent emerging frontiers in peptide therapeutics. 3