How do peptides work?

How Peptides Work: Biological Mechanisms and Clinical Applications

Peptides are short chains of amino acids (typically 2-50 amino acids) that function as signaling molecules by binding to cell surface receptors, initiating intracellular signal transduction cascades that regulate physiological processes including cardiovascular, gastrointestinal, and neurocranial systems. 1, 2

Fundamental Mechanism of Action

Receptor Binding and Signal Transduction

• Peptides act as ligands that bind to G-protein coupled receptors (GPCRs) on cell surfaces, triggering signal transduction through multiple layers of phosphorylating enzymes and binding proteins in a cascading sequence. 3
• The binding initiates intracellular signals that are transduced through scaffolding proteins acting in protein-to-protein interactions, ultimately modulating cellular responses. 3
• Peptides serve as hormones, neurotransmitters, and signal transducing factors that regulate or mediate physiological processes throughout the body. 3, 2

Structural Basis for Function

• Peptides occupy a unique chemical space between small molecules and larger proteins, with their molecular size (typically 2-50 amino acids) providing optimal characteristics for receptor binding and biological activity. 1, 2
• They can be arranged as linear chains or cycles and include post-translational modifications, unusual amino acids, and stabilizing motifs that enhance their function. 2
• Peptides bind to receptors at specific sites, often targeting "hot spots" that comprise only a small part of the binding interface but account for 80% of the binding energy. 4

Specific Mechanisms in Immune Function

MHC Class I Pathway

• For immune peptides, fragments are generated from cytoplasmic proteins through proteasomal cleavage, then transported by TAP protein into the endoplasmic reticulum where they are loaded onto MHC molecules for antigen presentation. 5
• The immunoproteasome degrades proteins into peptides, with specific cleavage sites determining which peptide fragments become available for immune recognition. 5

MHC Class II Pathway

• Exogenous peptides enter antigen-presenting cells through endocytosis, where increasing acidity activates serine, aspartic, and cysteine proteases that degrade proteins into potential antigens. 5
• Unlike Class I processing where proteins denature, Class II cleavage occurs on folded proteins, with secondary structures playing critical roles in determining cleavage patterns. 5

Therapeutic Mechanisms

Direct Receptor Modulation

• Peptides function as agonists or antagonists by mimicking natural ligands, allowing them to either activate or block receptor-mediated physiological processes. 3, 4
• Their small size enables them to disrupt functional protein complexes through specific binding properties, interfering with protein-protein interactions essential for disease processes. 4

Natriuretic Peptide Example (BNP)

• BNP is released from cardiac ventricles in response to increased wall stress and binds to NPR-A receptors, activating cyclic guanosine monophosphate as a second messenger to promote natriuresis, diuresis, and vasodilation. 5, 6
• BNP antagonizes the renin-angiotensin-aldosterone and sympathetic nervous systems, modulates myocardial structure through anti-proliferative effects, and acts as a neurotransmitter in the central nervous system. 5

Clinical Delivery and Bioavailability

Challenges and Solutions

• Short hydrophilic peptides generally do not cross plasma membranes independently, requiring carrier systems like liposomes, nanoparticles, or fusion to protein transduction domains for intracellular delivery. 4
• For extracellular targets like cell surface receptors, peptides have direct access and can function immediately upon administration. 4
• Intranasal delivery has been explored to overcome poor brain penetration, with peptides like Peptide T demonstrating antiviral benefits through this route. 5

Stability Enhancement

• Stabilization is achieved through introduction of non-natural amino acids to create peptidomimetics resistant to cellular proteases, significantly extending biological half-life. 4
• Synthetic long peptides (15-30 amino acids) require internalization and processing by professional antigen-presenting cells, providing greater efficacy than short peptides which can induce tolerance. 5

Critical Considerations

Factors Affecting Peptide Function

• Peptide manufacturability depends on chemical properties including hydrophobic sequences, cysteine residues, and specific amino acid bonds that can complicate synthesis or cause solubility problems. 5
• For immune peptides, the location of mutations within anchor residues for specific HLA alleles significantly impacts binding affinity and immunogenicity. 5

Common Pitfalls

• Peptide processing and cleavage must be considered when predicting biological activity, as inappropriate proteasomal cleavage can prevent generation of functional peptides. 5
• Secondary structure considerations are critical for Class II peptides, as cleavage occurs on folded proteins rather than denatured ones. 5