Why are peptides important?

Why Peptides Are Important in Medicine

Peptides serve as critical biological signaling molecules and therapeutic agents that bridge the gap between small molecules and large proteins, offering unique advantages in precision medicine and disease treatment.

Core Biological Functions

Peptides function as essential signaling entities across all domains of life, mediating protein-protein interactions that are indispensable for biological processes. 1 They carry fundamental molecular information and act as fragments of proteins that execute diverse biological functions throughout the body. 1

Diagnostic Applications

• Natriuretic peptides (BNP and NT-proBNP) demonstrate superior diagnostic accuracy for heart failure compared to clinical judgment alone, with ROC curves of 0.94 versus 0.90 (p=0.006). 2
• BNP <100 pg/mL effectively excludes acute heart failure with 90% sensitivity and 94% negative predictive value, while BNP >400 pg/mL strongly indicates heart failure with a positive likelihood ratio exceeding 10. 2
• NT-proBNP <300 pg/mL in non-acute settings has a 98% negative predictive value for heart failure, making cardiac failure highly unlikely. 3
• These peptide biomarkers provide convenient, noninvasive approaches to detect disease severity and guide management decisions in heart failure. 4

Prognostic Significance

• For each 100 pg/mL increase in BNP, the relative risk of death increases by approximately 35% over 1.5-3 years (95% CI: 22-49%). 2
• Elevated natriuretic peptide levels predict increased risk of death, heart failure hospitalization, atrial fibrillation, and stroke. 2
• Elevated preoperative BNP predicts postoperative cardiovascular events in non-cardiac surgery, helping identify high-risk surgical patients. 2

Therapeutic Advantages

Peptides offer an optimal balance of specificity, safety, and molecular size, providing greater precision in targeting specific receptors with fewer off-target effects and reduced toxicity compared to small-molecule drugs. 5

Key Therapeutic Benefits

• Peptides demonstrate higher efficiency in tissue penetration and cell internalization compared to antibodies, despite having lower affinity and shorter half-life. 6
• They exhibit enhanced tissue penetration with simpler, cheaper manufacturing processes and lower immunogenicity than larger biologics. 5
• Peptides are highly selective and efficacious while remaining relatively safe and well-tolerated. 7
• The global peptide therapeutics market is projected to exceed USD 50 billion by 2024, with approximately 100 peptides having attained clinical approval in major markets. 5

Clinical Applications

• Peptides serve as tumor-homing ligands for delivering carriers (nanoparticles, extracellular vesicles, cells) and cargoes (cytotoxic peptides, radioisotopes) to tumors. 6
• They function as peptide-drug conjugates when conjugated with chemotherapeutic drugs via linkers. 6
• Peptides selectively bind to cell surface receptors including immune checkpoints, receptor kinases, and hormone receptors, blocking their biological activity or serving as hormone analogs. 6
• They treat metabolic disorders, cancer, and serve as antimicrobial and anti-inflammatory agents. 5

Immunological Importance

Peptides are central to antigen presentation pathways, where they bind MHC molecules for immune recognition and T cell activation. 4

MHC Class I Pathway

• Peptide fragments generated from cytoplasmic proteins are transported by TAP protein into the endoplasmic reticulum, where they load onto MHC molecules. 4
• Proteasomal cleavage, TAP transport, and MHC class I binding must all be considered for neoantigen prioritization in cancer immunotherapy. 4

MHC Class II Pathway

• Exogenous peptides enter endosomes of antigen-presenting cells through endocytosis and are processed by proteases in late endosomal compartments. 4
• Class-II-specific neoantigens show promising results in cancer immunotherapies, though this remains an active area of development. 4

Vaccine Design

• Synthetic long peptides (SLPs) of 15-30 amino acids are effective neoantigen delivery mechanisms in personalized immunotherapy, with greater efficacy than short peptides because they require internalization by professional APCs. 4
• Peptides can be delivered via multiple mechanisms including synthetic peptides, DNA, mRNA, viral vectors, and ex-vivo-loaded dendritic cell vaccines. 4

Critical Limitations and Solutions

Stability Challenges

• Poor chemical and physical stability, short circulating plasma half-life, and solubility issues require solutions before peptides can be widely used as therapeutics. 8
• Certain amino acid sequences make peptides difficult to synthesize, with longer peptides encountering solubility problems. 4
• N-terminal modifications (formylation, acetylation, methylation) help protect peptides from aminopeptidases. 4

Immunogenicity Concerns

• Administration of peptide-containing products may trigger development of antibodies, with 69% of patients developing measurable antibody titers in long-term studies. 9
• Antibody formation may be associated with loss of response to treatment. 9

Emerging Solutions

• Innovative drug delivery systems including nanoparticles, polymeric micelles, and nanogels address delivery challenges. 4
• Multifunctional and cell-penetrating peptides, along with peptide-drug conjugates, represent new approaches beyond traditional peptide design. 7
• Advanced nano-supramolecular technologies and smart bio-functional materials improve peptide delivery and efficacy. 1

Predictive Tools and Characterization

• PepAnalyzer and similar bioinformatic tools predict 15 different peptide properties including binding potential, half-life, transmembrane patterns, stability, charge, and molecular weights using only sequence information. 8
• These tools assist researchers and the pharmaceutical sector in peptide design and optimization. 8