reviewed april 2026|next review october 2026|88 physicians psi has verified|41996 published studies
Protegrin-1
Protegrin-1 (PG-1) is an 18-amino acid beta-hairpin antimicrobial peptide isolated from porcine leukocytes, with its synthetic analog iseganan (IB-367) having reached Phase III clinical trials for oral mucositis before failing the primary efficacy endpoint.
Evidence landscape: 41996 published studies
Published studies span antimicrobial peptide research, structural biology, and the iseganan clinical program. Phase III human data exists (failed).
- 12 Human
- 117 Animal
- 71 Reviews
- 41796 Other research
Not FDA-approved. Iseganan (IB-367), a synthetic protegrin derivative, was rejected by the FDA in 2002 after failing to demonstrate efficacy in Phase III oral mucositis trials. The original compound is a research peptide.
Not available as a therapeutic product. Research-grade material available for laboratory use. Iseganan development was discontinued after the Phase III failure.
Protegrin-1 is one of the most potent natural antimicrobial peptides characterized. It forms octameric pores in bacterial membranes. The beta-hairpin structure with two disulfide bonds provides exceptional stability. Despite strong in vitro data, the clinical derivative failed Phase III.
PSI Assessment
In laboratory studies, protegrin-1 is one of the most potent natural antimicrobial peptides ever characterized. It kills gram-positive and gram-negative bacteria, fungi, and enveloped viruses by assembling into ring-shaped pores in their cell membranes. A synthetic derivative called iseganan (IB-367) advanced to Phase III clinical trials for preventing oral mucositis in cancer patients receiving radiation therapy. The trial did not meet its primary efficacy endpoint, and the FDA rejected the application in 2002. The biology remains impressive. The clinical translation failed. Next-generation protegrin analogs are being developed, but no new clinical program has been registered.
One of the most potent natural antimicrobial peptides. Forms octameric pores in bacterial membranes. Clinical derivative iseganan failed Phase III for oral mucositis. Strong biology, failed translation.
The mechanism involves formation of octameric transmembrane pores. The amphipathic beta-hairpin structure inserts into bacterial lipid bilayers, and multiple protegrin molecules oligomerize to create ion channels that dissipate membrane potential, causing rapid bacterial cell death. Two disulfide bonds maintain the rigid beta-hairpin structure essential for pore-forming activity. This mechanism is distinct from the carpet model used by alpha-helical antimicrobial peptides like LL-37.
What the evidence supports
Protegrin-1 demonstrates potent broad-spectrum antimicrobial activity against gram-positive and gram-negative bacteria, fungi, and enveloped viruses in laboratory studies. The octameric pore-forming mechanism is structurally characterized. The beta-hairpin structure with two disulfide bonds provides stability. Iseganan (IB-367), a synthetic protegrin derivative, completed Phase III clinical trials for oral mucositis, providing human safety data even though the efficacy endpoint was not met.
What is not yet established
Clinical efficacy for any indication after the iseganan Phase III failure for oral mucositis. Whether next-generation protegrin analogs can overcome the clinical limitations that led to iseganan's failure. Selectivity between bacterial and mammalian cell membranes at therapeutic concentrations. Whether the in vitro potency translates to in vivo therapeutic utility.
Research Evidence
The findings below cover the antimicrobial mechanism, the iseganan clinical program, and the engineering of next-generation analogs.
Evidence by condition
Evidence dimensions across antimicrobial biology, oral mucositis, and drug-resistant infection research. The clinical program reached Phase III but failed the primary endpoint.
| Condition | Mechanism | Animal evidence | Human evidence | Replication |
|---|---|---|---|---|
| Antimicrobial Activity | ||||
| Oral Mucositis | ||||
| Drug-Resistant Infections | ||||
| AMP Engineering |
Protegrin-1 demonstrates potent broad-spectrum antimicrobial activity in laboratory studies, killing gram-positive bacteria, gram-negative bacteria, fungi, and enveloped viruses at low concentrations through an octameric pore-forming mechanism.
The in vitro potency is among the highest documented for natural antimicrobial peptides. The pore-forming mechanism is structurally characterized by NMR and molecular dynamics studies.
Iseganan (IB-367), a synthetic protegrin analog, completed Phase III clinical trials for prevention of oral mucositis in head and neck cancer patients receiving radiation therapy. The trial did not meet its primary efficacy endpoint.
The Phase III failure demonstrates the well-known gap between in vitro antimicrobial potency and clinical efficacy. Factors including drug delivery, tissue penetration, and the clinical setting all contribute to this translation challenge.
Next-generation protegrin analogs with improved selectivity and reduced hemolytic activity are being developed. Structure-activity studies have identified modifications that maintain antimicrobial potency while reducing toxicity to mammalian cells.
The analog development represents an attempt to overcome the limitations that contributed to iseganan's clinical failure. No new clinical program has been registered.
12 Human|117 Animal|71 Reviews
View all 41996 indexed studiesHow Protegrin-1 Works
Protegrin-1 is an 18-amino acid beta-hairpin antimicrobial peptide from porcine leukocytes. It forms octameric transmembrane pores in bacterial membranes, dissipating membrane potential and causing cell death. Two disulfide bonds maintain the rigid structure.
Protegrin-1 kills bacteria by assembling into ring-shaped pores in their cell membranes, punching holes that destroy the bacterial cell's ability to maintain itself. Two disulfide bonds lock the peptide into a rigid shape essential for this pore-forming activity.
For a more detailed view of the biology, here is what researchers have observed at the molecular level.
18-amino acid beta-hairpin peptide forming octameric pores in bacterial membranes.
What is Protegrin-1 being studied for?
Researchers are studying Protegrin-1 across several health conditions. Each condition below is labeled with the strength of evidence that exists for that specific use, not for Protegrin-1 overall. This means a compound can have human studies for one condition but only animal data for another.
Antimicrobial Activity
·Human TrialsPotent broad-spectrum activity against gram-positive and gram-negative bacteria including multidrug-resistant strains in laboratory studies. The pore-forming mechanism is structurally characterized.
Limitations: All antimicrobial data is from laboratory and animal model studies (animal research). The iseganan clinical failure demonstrates that in vitro potency does not guarantee clinical efficacy. Selectivity between bacterial and mammalian membranes at therapeutic concentrations is a concern.
Oral Mucositis
·Human TrialsIseganan (IB-367) completed Phase III clinical trials for prevention of oral mucositis in cancer patients. The trial did not meet its primary efficacy endpoint. The FDA rejected the application in 2002.
Limitations: The Phase III failure is definitive for the iseganan formulation and oral mucositis indication. Whether a different protegrin analog or formulation could succeed is speculative.
Drug-Resistant Infections
·Animal StudiesActivity against multidrug-resistant bacteria including MRSA in laboratory studies. The pore-forming mechanism makes resistance development theoretically less likely than for conventional antibiotics.
Limitations: No clinical data for drug-resistant infection treatment. Laboratory susceptibility data does not predict clinical outcome, as the iseganan experience demonstrated.
AMP Engineering
·Animal StudiesProtegrin-1 serves as a structural template for engineering next-generation antimicrobial peptides with improved selectivity and reduced toxicity. Structure-activity relationships are well-characterized.
Limitations: No next-generation protegrin analog has entered clinical trials. The engineering approach is at the animal study optimization stage.
Safety and Regulatory Status
FDA Status: Not FDA-approved. Iseganan (IB-367) was rejected by the FDA in 2002 after failing Phase III for oral mucositis. No new protegrin-based drug has entered clinical development.
Availability: Not available as a therapeutic product. Research material available for laboratory use. Iseganan development was discontinued.
Class context: Hemolytic activity at high concentrations was a known concern for protegrin-1. Iseganan was topically administered for oral mucositis, avoiding systemic exposure. Next-generation analogs aim to reduce mammalian cell toxicity while maintaining antimicrobial potency.
Iseganan (topical) was tolerable in Phase III trials. The program failed on efficacy, not safety. Hemolytic activity at high concentrations limits systemic use of unmodified protegrin-1. Next-generation analogs target improved selectivity.
Questions and Comparisons
Questions the evidence raises for a Protegrin-1 discussion.
Comparison and Related Research
Protegrin-1 is compared with other antimicrobial peptides and antibiotic-resistance research compounds.
Related compounds
Frequently Asked Questions
References
Each citation links to the original study on PubMed, the U.S. National Library of Medicine database.
- 1.Discovery paper identifying protegrins as a new family of antimicrobial peptides isolated from porcine leukocytes. Protegrin-1 (PG-1) showed broad-spectrum bactericidal activity against both Gram-positive and Gram-negative bacteria, with a distinctive beta-hairpin structure stabilized by two disulfide bonds.Kokryakov VN et al., 1993 in FEBS Lett. View on PubMed
- 2.Structure-activity study developing protegrin-1 analogs to understand the mechanism of bacterial membrane disruption. The research showed that PG-1 forms octameric pores in lipid bilayers, directly permeabilizing bacterial membranes. The beta-hairpin conformation and amphipathic charge distribution were both required for pore formation.Chen J et al., 2000 in Biophys J. View on PubMed
- 3.Systematic study of protegrin-1 analogs evaluating how structural modifications affect antimicrobial potency and mammalian cell toxicity. Several analogs retained broad-spectrum antimicrobial activity while showing reduced hemolytic effects, addressing one of the key barriers to clinical development of protegrin-based therapeutics.Aumelas A et al., 2006 in J Biol Chem. View on PubMed
- 4.Review of protegrin structure-function relationships across the five natural protegrin family members. PG-1 was the most potent and best-characterized, with minimum inhibitory concentrations in the low micromolar range against drug-resistant pathogens including MRSA and Pseudomonas aeruginosa. The review highlighted the therapeutic potential and the hemolytic toxicity challenge.Ostberg N et al., 2005 in Peptides. View on PubMed
Medical Disclaimer
This content is for educational and informational purposes only and does not constitute medical advice. The information presented reflects published research as indexed by PSI and should not be used to make treatment decisions. Always consult a qualified healthcare provider before starting, stopping, or modifying any treatment.