Drug peptide

Drug peptides are a class of compounds composed of amino acids linked by peptide bonds, typically consisting of 2 to 50 amino acids, developed for use as therapeutic drugs. They fall between traditional small molecule chemical drugs (molecular weight<500 Da) and large molecule biological drugs (such as antibodies, molecular weight>10000 Da), and are an important category of drugs.
 

Core features and advantages:
1. High specificity and potency: Peptide drugs can selectively bind to targets (such as receptors and enzymes) like natural ligands (such as hormones and cytokines), so they usually have strong therapeutic effects and relatively small side effects.
2. Good safety: Peptides are ultimately metabolized into amino acids in the body, usually without accumulated toxicity, and the metabolites are harmless.
3. Diverse designs: By arranging and combining amino acid sequences, peptides with specific spatial structures and functions can be designed to target "non drug" targets that are difficult for traditional small molecules to act on.
 

Main challenges:
1. Difficulty in oral administration: It is easily degraded by enzymes in the gastrointestinal tract and difficult to be absorbed through the intestinal wall.
2. Poor plasma stability: easily hydrolyzed by proteases in the blood, resulting in a short half-life.
3. Low membrane permeability: It is usually difficult to penetrate the cell membrane, so it mainly acts on targets on the cell surface (such as GPCRs, ion channels).
To overcome these challenges, drug development often employs strategies such as chemical modifications (such as PEGylation, fatty acid chain modification, cyclization, introduction of D-amino acids), novel drug delivery systems (such as injections, inhalers, transdermal patches), and development of peptide coupled drugs.
 

Main categories and examples of drug peptides
Some heavyweight or representative drug peptides classified by therapeutic field:
1. Metabolic diseases field
One of the most successful fields of peptide drugs.
·Glucagon like peptide-1 receptor agonist:
·Liraglutide, semaglutide, dulaglutide: These are GLP-1 analogs that activate GLP-1 receptors to promote insulin secretion, inhibit glucagon secretion, delay gastric emptying, and reduce appetite in a glucose concentration dependent manner. It is used to treat type 2 diabetes and obesity. Simeglutide (trade name Wegovy/Ozempic) is currently one of the most highly regarded drugs.

Semaglutide is a long-acting, selective, competitive GLP-1R agonist that can penetrate the blood-brain barrier. Semaglutide activates GLP-1R to promote insulin secretion, inhibit gastric emptying and appetite, while enhancing autophagy, inhibiting oxidative stress and apoptosis. Semaglutide also regulates mitochondrial function and lipid metabolism (such as reducing de novo fat production in the liver). Semaglutide has activities such as lowering blood sugar, weight loss, neuroprotection (such as improving motor function in Parkinson's disease models, reducing alpha synuclein aggregation), and improving hepatic steatosis. Semaglutide can be used in the research of neurodegenerative diseases and liver diseases, such as

type 2 diabetes, obesity, Parkinson's disease, metabolism related fatty liver disease (MASLD), and cancer.

In vitro research
1. Anti A β 25-35 injury experiment: Semaglutide (1-100 nM; 24 h) significantly increased the survival rate of SH-SY5Y cells, increased the expression of autophagy related proteins such as LC3II, Atg7, Beclin-1, and P62, inhibited Bax and upregulated Bcl-2, enhancing autophagy, inhibiting apoptosis, and protecting nerve cells.
2. Oral squamous cell carcinoma (OSCC) cell experiment: Semaglutide (5-40 μ M; 48 h) dose dependently inhibits the proliferation, migration, and invasion of Cal27 and HSC4 cells, upregulates E-cadherin and downregulates Vimentin, activates the P38 MAPK signaling pathway (increased p-P38 expression), and induces cell apoptosis.
 

In vivo research
When conducting animal experiments, subcutaneous or intraperitoneal injection can be chosen.
Transplanted tumor model of oral squamous cell carcinoma (OSCC)
Semaglutide (3 μ mol/kg; subcutaneous injection; 3 times a week; 3 weeks) significantly inhibited tumor volume growth in a nude mouse oral squamous cell carcinoma (OSCC) xenograft model, downregulated proliferation markers Ki67 and PCNA, upregulated pro apoptotic protein Bax and downregulated anti apoptotic protein Bcl xL, and induced tumor cell apoptosis by activating the P38 MAPK pathway.
Chronic MPTP induced Parkinson's disease model
Semaglutide (25 nmol/kg; intraperitoneal injection; Once every 2 days; 30 days) improved the chronic MPTP induced Parkinson's disease model and its motor dysfunction in mice, increased the number of tyrosine (TH) positive neurons in the substantia nigra, reduced alpha synuclein aggregation and glial cell activation, and lowered the level of oxidative stress marker 4-HNE.
Metabolic dysfunction associated fatty liver disease (MASLD) model
Semaglutide (25 μ g/kg/week+100 μ g/kg/week; Subcutaneous injection; Once a week; In the metabolic dysfunction associated fatty liver disease (MASLD) model of mice at 11 weeks, weight, blood glucose, and serum liver enzymes (ALT, AST, AP) were reduced, hepatic triglyceride deposition was decreased, hepatic steatosis and hepatocyte ballooning were improved, and de novo adipogenic markers Acaca and Scd1 were downregulated.
·Insulin and its analogues:
·Insulin aspart, insulin detec and insulin tegu: modify natural insulin through genetic engineering, change its onset time and duration of action, and provide more flexible and stable blood glucose control for diabetes patients.

2. In the field of tumor treatment
·Peptide receptor radionuclide therapy:
·Lutetium-177 DOTATATE: Used for the treatment of gastrointestinal and pancreatic neuroendocrine tumors positive for somatostatin receptors. Peptides (DOTATATE) serve as a "navigation system" targeting tumor cells, carrying radioactive isotopes (lutetium 177) as "warheads" to kill cells.
·Cytotoxic conjugate peptides:
·Miqin peptide: a cell wall peptide encapsulated in liposomes, used for the treatment of non metastatic osteosarcoma, which can activate macrophages to attack the tumor.
·Targeted therapeutic peptides:
·Kaffizomib: a proteasome inhibitor (modified tetrapeptidyl ketone) used to treat multiple myeloma.
3. Cardiovascular disease field
·Brain natriuretic peptide analog: Nasilide: recombinant human B-type natriuretic peptide, used for intravenous treatment of acute decompensated heart failure, can dilate blood vessels, promote urination, and reduce cardiac load.
·Anticoagulant peptide: Bivalirudin: a direct thrombin inhibitor (20 amino acids) used for anticoagulation in percutaneous coronary intervention therapy.
4. Antibacterial field
·Antimicrobial peptides or peptide antibiotics:
·Daptomycin: a cyclic peptide antibiotic that kills Gram positive bacteria, including methicillin-resistant Staphylococcus aureus, by disrupting the membrane potential of bacterial cells.
·Polymyxin B/E: a peptide antibiotic that is one of the "last line of defense" drugs for treating infections caused by multidrug-resistant Gram negative bacteria such as Acinetobacter baumannii and Pseudomonas aeruginosa.
5. Endocrine and reproductive fields
·Gonadotropin releasing hormone analogs:
·Leuprorelin and Goserelin: GnRH agonists. Long term use can inhibit the secretion of pituitary gonadotropin, which is used to treat prostate cancer, breast cancer, endometriosis and central precocious puberty.
·Somatostatin analogs:
·Octreotide and Lantreotide: Used to control symptoms of acromegaly and treat syndromes related to gastrointestinal, pancreatic, neuroendocrine tumors (such as carcinoid syndrome).
6. In the field of skeletal diseases
·Parathyroid hormone analogues:
·Teriparatide and Abalotide: are fragments of PTH or its related peptides that can promote bone formation and are used to treat severe osteoporosis.
7. Diagnostic reagents
·Radioactive labeled peptides:
·Gallium-68 DOTATATE/DOTATOC: Used for positron emission tomography imaging and localization diagnosis of neuroendocrine tumors expressing somatostatin receptors.

Drug peptides have become an indispensable part of modern drug development due to their high selectivity, efficacy, and good safety. With the rapid development of technologies such as oral peptides, peptide coupled drugs, bifunctional/multifunctional peptides, and peptide design based on computers and AI, the application prospects of drug peptides will be even broader. They are growing from the "middle ground" between small molecule and biomacromolecule drugs to a mainstream drug category that can accurately target refractory diseases and has unique therapeutic advantages.