RPEP-00072 · 1988Human placental aminopeptidase M completely degraded Met-enkephalin and Leu-enkephalin into their five constituent amino acids. The degradation rate was measured by tracking tyrosine release.
The degradation speed ranked: Met-enkephalin (fastest) > Leu-enkephalin > beta-neoendorphin > dynorphin > beta-endorphin (slowest).
Smaller, simpler peptides were degraded faster than larger, more complex ones. Met-enkephalin (5 amino acids) was destroyed faster than beta-endorphin (31 amino acids).
Furuhashi, M; Mizutani, S; Kurauchi, O; Kasugai, M; Narita, O; Tomoda, Y · In Vitro
RPEP-00244 · 1992Chimeric peptides coupling opioid peptides to BBB transport vectors allow brain delivery of enkephalin and dynorphin analogs in vivo. The strategy has advantages for addiction drug development.
Pardridge, W M · Review
RPEP-00295 · 1994L-692,585 produced 4.3 to 7-fold increases in peak GH with maintained efficacy over 15 days of daily dosing and elevated IGF-1 by day 15.
Jacks, T; Hickey, G; Judith, F; Taylor, J; Chen, H; Krupa, D; Feeney, W; Schoen, W; Ok, D; Fisher, M · Animal Study
RPEP-00299 · 1994Peptidase inhibitor mixture enhanced antinociception from met-enkephalin, beta-endorphin, and electroacupuncture, but not dynorphin-(1-13).
Kishioka, S; Miyamoto, Y; Fukunaga, Y; Nishida, S; Yamamoto, H · Animal Study
RPEP-00314 · 1995ACBC-containing model peptides adopted characteristic stable conformations (helical and extended) that could be leveraged for peptide drug design.
Balaji, V N; Ramnarayan, K; Chan, M F; Rao, S N · In Vitro
RPEP-00333 · 1995Hydrophobic i,i+5 and i,i+8 interactions provide measurable stabilization to alpha-helix structures, with the hydrophobic staple motif contributing to helix nucleation.
Muñoz, V; Serrano, L · In Vitro
RPEP-00334 · 1995The hydrophobic-staple motif (i,i+5 interaction at helix N-terminus) was discovered, validated by NMR, and shown to stabilize alpha-helices and define their N-terminal boundaries.
Muñoz, V; Blanco, F J; Serrano, L · In Vitro
RPEP-00340 · 1995Eschscholtzia californica and Corydalis cava extracts inhibited peroxidase- and tyrosinase-mediated dimerization and oxidation of enkephalin peptides.
Reimeier, C; Schneider, I; Schneider, W; Schäfer, H L; Elstner, E F · In Vitro
RPEP-00348 · 1995IGF-1 had a half-life of only 2 minutes in the duodenum and ileum, but casein protein significantly protected it from degradation in the gut.
Xian, C J; Shoubridge, C A; Read, L C · Animal Study
RPEP-00377 · 1996Endogenous opioid peptides contribute to post-tetanic inhibition of gut muscle contractions, and peptidase inhibitors enhance this effect by protecting naturally released peptides from degradation.
Ozaki, M; Masuda, Y; Yamamoto, H · In Vitro
RPEP-00389 · 1996Peptidase inhibitors significantly prolonged the antinociceptive effect of intrathecally administered dynorphin A (0.5-2 nmol) and dynorphin B (2-8 nmol) in the formalin test.
Tan-No, K; Taira, A; Sakurada, T; Inoue, M; Sakurada, S; Tadano, T; Sato, T; Sakurada, C; Nylander, I; Silberring, J; Terenius, L; Kisara, K · Animal Study
RPEP-00466 · 1998Ipamorelin demonstrated approximately 20% nasal bioavailability in rats, superior to GHRP-2, GHRP-6, and two other peptides, supporting its potential for non-invasive nasal delivery.
Johansen, P B; Hansen, K T; Andersen, J V; Johansen, N L · Animal Study
RPEP-00472 · 1998Lactoferricin was detected and quantified in human serum for the first time using SELDI affinity mass spectrometry, establishing its natural occurrence in the bloodstream.
Kuwata, H; Yip, T T; Yip, C L; Tomita, M; Hutchens, T W · In Vitro
RPEP-00473 · 1998Affinity mass spectrometry enabled direct detection and quantification of lactoferricin and multiple lactoferrin-derived peptide fragments in human gastric contents, revealing the peptide generation process in detail.
Kuwata, H; Yip, T T; Yip, C L; Tomita, M; Hutchens, T W · In Vitro
RPEP-00474 · 1998Direct detection of lactoferricin generation in the human stomach after oral lactoferrin ingestion, providing the first in-vivo evidence of this bioactive peptide's natural formation during digestion.
Kuwata, H; Yip, T T; Tomita, M; Hutchens, T W · Clinical Trial
RPEP-00494 · 1998Dynorphin B and beta-endorphin were confirmed in human plasma by HPLC and mass spectrometry, while dynorphin A was undetectable due to rapid enzymatic conversion to leu-enkephalin in blood.
Silberring, J; Li, Y M; Terenius, L; Nylander, I · In Vitro
RPEP-00801 · 2003Capromorelin showed potent GHS-R binding (Ki=7 nM), oral GH-releasing activity in rats, 60% oral bioavailability in dogs, and IGF-1 elevation with repeated dosing, emerging as a clinical development candidate.
Carpino, Philip A; Lefker, Bruce A; Toler, Steven M; Pan, Lydia C; Hadcock, John R; Cook, Ewell R; DiBrino, Joseph N; Campeta, Anthony M; DeNinno, Shari L; Chidsey-Frink, Kristin L; Hada, William A; Inthavongsay, John; Mangano, F Michael; Mullins, Michelle A; Nickerson, David F; Ng, Oicheng; Pirie, Christine M; Ragan, John A; Rose, Colin R; Tess, David A; Wright, Ann S; Yu, Li; Zawistoski, Michael P; DaSilva-Jardine, Paul A; Wilson, Theresa C; Thompson, David D · Animal Study
RPEP-00809 · 2003Orally active GH secretagogues and cortistatin (a somatostatin-related peptide) both target the ghrelin receptor, expanding the receptor's known ligand repertoire and therapeutic targeting possibilities.
Deghenghi, Romano; Broglio, Fabio; Papotti, Mauro; Muccioli, Giampiero; Ghigo, Ezio · Review
RPEP-00903 · 2004Intranasal PT-141 induced dose-dependent erectile responses in both healthy men and Viagra-responsive ED patients in a double-blind, placebo-controlled trial, with rapid onset and acceptable safety — validating intranasal melanocortin ED therapy.
Diamond, L E; Earle, D C; Rosen, R C; Willett, M S; Molinoff, P B · RCT
RPEP-00920 · 2004Multiple novel ghrelin analogs were designed with improved pharmacokinetic properties (longer half-life, better stability) and selectivity profiles compared to native ghrelin, maintaining GH-releasing and appetite effects in animal models.
Halem, Heather A; Taylor, John E; Dong, Jesse Z; Shen, Yeelana; Datta, Rakesh; Abizaid, Alfonso; Diano, Sabrina; Horvath, Tamas; Zizzari, Philippe; Bluet-Pajot, Marie-Thèrèse; Epelbaum, Jacques; Culler, Michael D · Animal Study
RPEP-00934 · 2004Dynamic compressive loading of chondrocytes in self-assembling peptide scaffolds maintained or enhanced cartilage matrix (proteoglycan, collagen) production, demonstrating the scaffold's suitability for the mechanically demanding joint environment.
Kisiday, John D; Jin, Moonsoo; DiMicco, Michael A; Kurz, Bodo; Grodzinsky, Alan J · In Vitro
RPEP-00969 · 2004SC PT-141 induced dose-dependent erectile responses in ED patients (double-blind, placebo-controlled) with characterized pharmacokinetics, acceptable safety, and practical SC delivery — advancing toward clinical approval.
Rosen, R C; Diamond, L E; Earle, D C; Shadiack, A M; Molinoff, P B · RCT
RPEP-01020 · 2005Recombinant thymosin alpha-1 produced in Pichia pastoris yeast expression system showed biological activity equivalent to chemically synthesized peptide, establishing a cost-effective, scalable manufacturing platform for clinical-grade thymosin alpha-1.
Chen, Feng; Chen, Xiang-Ming; Chen, Zhi; Jiang, Han-Liang; Pan, Xiao-Ping; Hu, Zhong-Rong; Liu, Rong-Hua; Chen, Xiao-Ming · In Vitro
RPEP-01021 · 2005Oral thymosin alpha-1 enhanced T-cell function, NK cell activity, and cytokine production in mice, demonstrating that the peptide retains immunomodulatory activity after oral administration — a practical advance for non-injectable immune therapy.
Chen, Xiang-Ming; Jiang, Han-Liang; Zhou, Lin-Fu; Pan, Xiao-Ping; Hu, Zhong-Rong; Liu, Rong-Hua; Chen, Xiao-Ming; Chen, Zhi · Animal Study
RPEP-01075 · 2005Glycosylation of opioid and other neuropeptides enhanced BBB penetration, metabolic stability, and analgesic potency after peripheral administration, establishing glycopeptides as a practical strategy for delivering peptide drugs to the brain.
Polt, Robin; Dhanasekaran, Muthu; Keyari, Charles M · Review
RPEP-01126 · 2006Updated cyclotide drug scaffold review covering recent advances: new grafting applications for diverse therapeutic targets, confirmed oral stability and bioavailability, expanded bioactivity profiles, and progress toward clinical macrocyclic peptide drugs.
Craik, David J; Cemazar, Masa; Daly, Norelle L · Review
RPEP-01276 · 2007Hydroxyproline-containing di- and tripeptides from orally ingested gelatin hydrolysate were detected in human plasma, with food-grade collagen hydrolysate producing higher peptide blood levels than gelatin — confirming oral collagen peptide bioavailability.
Ohara, Hiroki; Matsumoto, Hitoshi; Ito, Kyoko; Iwai, Koji; Sato, Kenji · Clinical Trial
RPEP-01320 · 2008N-methylation of peptide backbone amides improves oral bioavailability, proteolytic stability, membrane permeability, and conformational rigidity — the key chemical modification enabling oral peptide drugs, validated by cyclosporine and being applied to new therapeutic peptides.
Chatterjee, Jayanta; Gilon, Chaim; Hoffman, Amnon; Kessler, Horst · Review
RPEP-01358 · 2008Mu-opioid peptide agonists and antagonists showed variable Caco-2 monolayer permeability, with some achieving transcellular transport — assessing oral bioavailability potential and identifying which opioid peptide structures achieve gut barrier crossing.
Iwan, Małgorzata; Jarmołowska, Beata; Bielikowicz, Krzysztof; Kostyra, Elzbieta; Kostyra, Henryk; Kaczmarski, Maciej · In Vitro
RPEP-01385 · 2008GHK-Cu and other peptide-copper complexes demonstrated measurable skin penetration and bioactive copper delivery to dermal layers, validating the bioavailability of topical copper peptide formulations for skin anti-aging and wound healing applications.
Mazurowska, Lena; Mojski, Miroslaw · In Vitro
RPEP-04829 · 2020Of 27 bioactive peptides with chemical protection at both ends (to resist degradation), 13 remained stable after 72 hours at body temperature in horse plasma. The other 14 broke down to varying degrees.
The researchers identified specific breakdown products (catabolites) for all 14 unstable peptides, including novel catabolites never previously reported for chemotactic peptide, DALDA, dmtDALDA, deltorphins I and II, and several dermorphin analogs.
Key stability rules emerged: a D-amino acid (mirror image of normal) at position 2 or position 1 of a peptide, or next to its C-terminus, protected that end from degradation. But a D-amino acid at position 3 did not help. N-terminal modifications like pyroglutamic acid or N-methylation did not protect the N-terminal end. A C-terminal ethylamide group did protect against carboxypeptidase attack. The C-terminal lysine amide in DALDA, dmtDALDA, and Lys7-dermorphin was unexpectedly vulnerable to plasma enzymes.
Guan, Fuyu; Fay, Savannah; Li, Xiaoqing; You, Youwen; Robinson, Mary A · Analytical/Experimental
RPEP-04834 · 2020The researchers used a technique called hierarchical imprinting to create synthetic polymers with binding pockets shaped to grab the FLAG peptide tag (DYKDDDDK). They tested two different silane coatings to orient the template peptide correctly during manufacturing.
The version made with AETAZS silane performed significantly better: 87.4% recovery of the FLAG tag versus only 4.1% non-specific binding. The AEAPMS version recovered 73.4% but had much higher non-specific binding at 23.2%.
Computational modeling revealed why orientation matters. When the template peptide is properly anchored, the imprinted cavities form more precise shapes that better match the target.
Gómez-Arribas, Lidia N; Darder, María Del Mar; García, Nuria; Rodriguez, Yoel; Urraca, Javier L; Moreno-Bondi, María C · In Vitro (Materials Science)
RPEP-04839 · 2020The protocol addresses a technical challenge in ADC development: hydrophobic drug-loaded peptides tend to precipitate out of solution during standard peptide mapping, making them invisible to mass spectrometry.
The improved method includes modifications to sample preparation that keep hydrophobic drug-loaded peptides dissolved, enables better chromatographic separation so these peptides are not lost, and uses diagnostic fragmentation ions from the drug payload to unambiguously identify conjugation sites in the LC-MS/MS data.
This allows researchers to map exactly which amino acids on the antibody have drugs attached, which is critical for understanding ADC potency and safety.
Han, Linjie; Zhao, Yanqun; Zhang, Qunying · Methods Paper
RPEP-04875 · 2020All variants had identical amino acid composition (same letters, different order), yet behaved very differently:
A6G: RGD at this position disrupted beta-sheet formation, preventing proper self-assembly.
A10G and A14G: both formed assembled nanofibers and produced hydrogels with higher viscoelasticities. Both showed substantial cell adhesion, performing as effective extracellular matrix mimics.
Other variants: significantly reduced cell adhesion despite containing the same RGD sequence.
The key insight is that the higher-order supramolecular structure strongly influences RGD functionality. Simply having the RGD sequence is not enough; it must be positioned where it does not disrupt self-assembly and where it is properly displayed on the nanofiber surface for integrins to access.
Ishida, Atsuya; Oshikawa, Mio; Ajioka, Itsuki; Muraoka, Takahiro · Biomaterials (In Vitro)
RPEP-04877 · 2020Exenatide is a peptide drug given by injection because it is destroyed in the gut and cannot cross the intestinal wall. Hydrophobic ion pairing (HIP) makes peptides lipophilic by pairing them with surfactant counterions.
Two surfactant types were tested: cationic THA (tetraheptylammonium bromide) and anionic DOC (sodium docusate). Both formed stable complexes with exenatide.
Exenatide-THA was more lipophilic (log D of 2.29 in simulated intestinal fluid vs 1.2 for exenatide-DOC). When loaded into lipid nanocarriers (41% Capmul MCM, 15% Captex 355, 40% Cremophor RH, 4% propylene glycol), the THA formulation showed:
- 10-fold enhancement in intestinal apparent membrane permeability vs free exenatide
- 28.0% ± 5.2% relative oral bioavailability in healthy rats
The DOC formulation achieved 3-fold permeability enhancement and 16.3% ± 6.6% bioavailability.
Neither formulation caused significant hemolytic activity at 0.25% concentration, indicating safety for oral use.
Ismail, Ruba; Phan, Thi Nhu Quynh; Laffleur, Flavia; Csóka, Ildikó; Bernkop-Schnürch, Andreas · Pharmaceutical Formulation + Animal Pharmacokinetics
RPEP-04880 · 2020This is the first demonstration that protein-peptide coassembly can induce gelation in a non-gelator peptide. The key findings:
A dipeptide that forms aggregates but not gels when alone was transformed into a fiber-forming hydrogel when proteins were added. The protein-peptide interactions converted aggregate-like structures into ordered fibrillar nanostructures.
The interactions were purely non-covalent (electrostatic, hydrophobic, hydrogen bonding). Biolayer interferometry and molecular docking confirmed dissociation constants and binding energies consistent with non-specific protein-peptide interactions.
Tunability: different proteins had different binding affinities to the peptide, producing gels with different mechanical and structural properties at the same peptide concentration. Simply changing the protein type or concentration tuned the gel.
Enzyme entrapment: an enzyme protein was successfully trapped within the gel network during coassembly without losing catalytic activity. This creates a scaffold that can both provide structural support and perform chemical reactions.
Jain, Rashmi; Pal, Vijay Kumar; Roy, Sangita · Biomaterials (Proof Of Concept)
RPEP-05017 · 2020Molecular grafting of bioactive epitopes into cyclotide scaffolds produces GPCR ligands with improved oral activity, enzymatic stability, and selectivity compared to linear peptide counterparts.
Muratspahić, Edin; Koehbach, Johannes; Gruber, Christian W; Craik, David J · Review
RPEP-05079 · 2020Polyphenol-bioactive peptide interactions during digestion can alter the bioavailability and biological function of both compounds, with implications for functional food and nutraceutical design.
Pérez-Gregorio, Rosa; Soares, Susana; Mateus, Nuno; de Freitas, Victor · Review
RPEP-05102 · 2020Smaller vesicles suppressed CPP cytolysis despite higher membrane curvature, because reduced lipid mobility in smaller vesicles restricts the local phase transitions required for CPP membrane penetration.
Sakamoto, Kazutami; Kitano, Takeshi; Kuwahara, Haruka; Tedani, Megumi; Aburai, Kenichi; Futaki, Shiroh; Abe, Masahiko; Sakai, Hideki; Ohtaka, Hiroyasu; Yamashita, Yuji · In Vitro
RPEP-05103 · 2020CPP cytolysis occurs in two steps: rapid adsorption (saturated within 10 min) followed by linear-rate internalization dependent on osmotic pressure. The mechanism involves Lα to Mesh1 lipid phase transition creating punctured bilayer morphologies.
Sakamoto, Kazutami; Morishita, Taku; Aburai, Kenichi; Sakai, Kenichi; Abe, Masahiko; Nakase, Ikuhiko; Futaki, Shiroh; Sakai, Hideki · In Vitro
RPEP-05291 · 2021Oral octreotide using TPE technology achieved therapeutic endpoints in Phase III trials with ~0.7% relative oral bioavailability, requiring 20 mg capsules compared to 0.1 mg subcutaneous injections.
Brayden, David J; Maher, Sam · Review
RPEP-05343 · 2021Intranasal delivery of insulin and glucagon-like peptides demonstrates improved therapeutic levels and patient compliance, with drugs transported through epithelial tight junctions via the paracellular route.
Dholakia, Jheel; Prabhakar, Bala; Shende, Pravin · Review
RPEP-05476 · 2021Comparison of human liver S9, hepatocyte spheroids, and other in vitro systems revealed model-dependent differences in peptide metabolism prediction, informing best practices for peptide drug development.
Jyrkäs, Juha; Tolonen, Ari · In Vitro Comparative Study
RPEP-05509 · 2021CPPs enhance diabetes treatment by: (1) improving hypoglycemic drug effectiveness, (2) facilitating insulin delivery, (3) synergizing with immunosuppressants for islet transplantation, (4) prolonging drug pharmacokinetics, and (5) retarding diabetic nephropathy.
Korivi, Mallikarjuna; Huang, Yue-Wern; Liu, Betty R · Review
RPEP-05533 · 2021Cyclosporin O derivatives demonstrated that intramolecular hydrogen bonds and conformational chameleonicity determine membrane permeability and cyclophilin A binding. Conformation-permeability-binding relationships were mapped with PK profiling.
Lee, Dongjae; Lee, Sungjin; Choi, Jieun; Song, Yoo-Kyung; Kim, Min Ju; Shin, Dae-Seop; Bae, Myung Ae; Kim, Yong-Chul; Park, Chin-Ju; Lee, Kyeong-Ryoon; Choi, Jun-Ho; Seo, Jiwon · Preclinical
RPEP-05549 · 2021Lipophilic salt forms of octreotide in lipid-based formulations improved enzymatic stability in GI lumen and intestinal membrane permeability, addressing both major barriers to oral peptide delivery.
Li, Peng; Ford, Leigh; Haque, Shadabul; McInerney, Mitchell P; Williams, Hywel D; Scammells, Peter J; Thompson, Philip E; Jannin, Vincent; Porter, Christopher J H; Benameur, Hassan; Pouton, Colin W · Preclinical
RPEP-05662 · 2021Oral delivery of peptide drugs faces three main barriers: enzymatic degradation (stomach acid and enzymes break them apart), poor membrane permeability (they are too large and charged to cross the gut lining), and instability (they unfold and lose function).
Computer-aided drug design (CADD) addresses these by modeling molecular interactions at the atomic level. Researchers can simulate how a peptide interacts with its receptor, screen formulation ingredients for compatibility, and predict which chemical modifications might improve stability or absorption.
The review highlights that CADD can pre-screen excipients (inactive ingredients in the formulation) and predict absorption before expensive lab experiments. This speeds up development and reduces costs for oral peptide formulations.
Pandya, Anjali K; Patravale, Vandana B · Review
RPEP-05724 · 2021Localized enzyme-assisted self-assembly produced peptide-based supramolecular hydrogel coatings whose properties could be precisely tuned by varying hyaluronic acid concentration. Coating thickness ranged from 18 µm (at 10 mg/mL HA) to 41 µm (at 2 mg/mL HA), while the elastic modulus decreased from 2 kPa to 0.2 kPa as HA concentration increased.
Higher HA concentrations caused peptide nanofibers to collapse into larger microstructures, fundamentally altering the internal architecture of the hydrogel. Despite these structural changes, all formulations supported NIH 3T3 fibroblast viability and adhesion.
Rodon Fores, Jennifer; Bigo-Simon, Alexis; Wagner, Déborah; Payrastre, Mathilde; Damestoy, Camille; Blandin, Lucille; Boulmedais, Fouzia; Kelber, Julien; Schmutz, Marc; Rabineau, Morgane; Criado-Gonzalez, Miryam; Schaaf, Pierre; Jierry, Loïc · In Vitro
RPEP-05771 · 2021After two-step chromatographic purification, collagen hydrolysate fractions from Clarias batrachus (C2) and Pangasius pangasius (P2) fish skin showed potent anti-inflammatory activity in LPS-activated RAW 264.7 macrophage cells. The active peptides were in the 1–3 kDa molecular weight range.
The C2 fraction reduced TNF-α gene expression to a 1.6-fold difference and IL-6 expression to a 30-fold difference compared to LPS stimulation alone. The P2 fraction reduced TNF-α to a 1.0-fold difference (essentially to baseline) and IL-6 to a 40-fold difference.
Both fractions also suppressed inflammatory proteins including TNF-α, IL-6, NFκB, and phosphorylated IκB (p-IκB), confirming the anti-inflammatory activity operates through the NFκB signaling pathway.
Sivaraman, K; Shanthi, C · In Vitro
RPEP-09102 · 2024HNSS showed a 2-fold improvement in brain distribution compared to HNG alone. Its structure mimics cell-penetrating peptides, which explains the enhanced brain entry.
Inside the brain, HNSS worked on multiple fronts. It targeted mitochondria and scavenged reactive oxygen species (damaging molecules). It activated the STAT3 pathway, which helps cell survival. It also blocked amyloid beta from clumping into the toxic oligomers and fibrils that characterize Alzheimer's. HNSS reduced amyloid deposits in neurons and helped immune cells in the brain (microglia) clear amyloid.
In 3xTg-AD transgenic mice (a standard Alzheimer's model), HNSS treatment prevented brain neuron loss and improved cognitive performance on memory tests.
Qian, Kang; Yang, Peng; Li, Yixian; Meng, Ran; Cheng, Yunlong; Zhou, Lingling; Wu, Jing; Xu, Shuting; Bao, Xiaoyan; Guo, Qian; Wang, Pengzhen; Xu, Minjun; Sheng, Dongyu; Zhang, Qizhi · Animal Study