Human gastric juice contains protein BPC, which exhibits a wide range of biological activities. The 15-amino acid fragment (BPC 157) and its analogues were synthesized using SPPS on a preloaded Boc-Val-HYCRAMTM polymeric resin (the combination of Boc- and Fmoc-chemistry was used) and a preloaded Fmoc-Val-SASRINTM polymeric resin (the Fmoc-chemistry was used). Yields, chromatographic purities and costs for synthesis of equal mmolar amounts of compounds on both polymeric resins were compared.
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... BPC-157 may be prepared using solidphase peptide synthesis (SPPS). In SPPS, amino acids are added stepwise onto a resin carrier, with protecting groups such as Boc or Fmoc and the use of coupling reagents like DIC/HOBt and HATU to activate the carboxyl group [18]. The fully assembled peptide is subsequently cleaved from the resin for further purification and processing [19]. ...
Claire Yuan Ariana Demers
Victor Silva Christopher L. Robinson
Body Protective Compound-157 (BPC-157) is a synthetic pentadecapeptide derived from gastric proteins that has demonstrated notable reparative and anti-inflammatory properties across diverse preclinical models. Experimental evidence reveals that BPC-157 supports angiogenesis, collagen synthesis, fibroblast activity, and modulation of nitric oxide pathways, contributing to enhanced healing of muscle, tendon, ligament, bone, and gastrointestinal tissue. Studies also report reduced inflammatory cytokine activity, improved microvascular integrity, and beneficial effects on pain modulation through peripheral and dopaminergic mechanisms. Although animal data indicate favorable safety and pharmacokinetics, human research remains limited to small pilot studies investigating musculoskeletal pain, interstitial cystitis, and intravenous administration, all suggesting potential therapeutic value without reported major adverse effects. However, inconsistent preparation standards, limited clinical validation, and regulatory restrictions underscore the need for rigorous controlled trials. BPC-157 remains a promising candidate for regenerative medicine, yet comprehensive evaluation is required before clinical translation can be recommended.
Michalina Józwiak Marta Bauer Wojciech Kamysz
Patrycja Kleczkowska
BPC 157, known as the “Body Protection Compound”, is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other drugs, BPC 157 has a desirable safety profile, since only a few side effects have been reported following its administration. Nevertheless, this compound was temporarily banned by the World Anti-Doping Agency (WADA) in 2022 (it is not currently listed as banned by the WADA). However, it has not been approved for use in standard medicine by the FDA and other global regulatory authorities due to the absence of sufficient and comprehensive clinical studies confirming its health benefits in humans. In this review, we summarize information on the biological activities of BPC 157, with particular reference to its mechanism of action and probable toxicity. This generated the attention of experts, as BPC 157 has been offered for sale on many websites. We also present recent interest in BPC 157 as reflected in a number of patent applications and granted patents.
Xiao-Chang Xue Yong-Jie Wu Ming-Tang Gao Ying-Qi Zhang
To investigate the protective effects of gastric pentadecapeptide BPC 157 on acute and chronic gastric ulcers in rats and to compare the results in therapy of human gastric ulcers by different administration methods. Gastric pentadecapeptide BPC 157 was administered (initial single or continuous administration) into rats either intragastrically or intramuscularly before (induced acute gastric ulcer) or after (induced chronic gastric ulcer) the applications of inducing agents, and each animal was sacrificed to observe the protective effects of BPC 157 on gastric ulcers. Both intramuscular (im) and intragastric (ig) administration of BPC 157 could apparently reduce the ulcer area and accelerate the healing of induced ulcer in different models and the effect of im administered BPC 157 was better than that of ig. The rats treated with higher dosages (400 ng/kg, 800 ng/kg) of BPC 157 (im and ig) showed significantly less lesion (P<0.01 vs excipient or saline control), the inhibition ratio of ulcer formation varied between 45.7% and 65.6%, from all measurements except 400 ng/kg BPC 157 in pylorus ligation induced model (P<0.05), in which the inhibition rate was 54.2%. When im administered (800 ng/kg BPC 157) in three models, the inhibition ratio of ulcer formation was 65.5%, 65.6% and 59.9%, respectively, which was better than that of famotidine (its inhibition rate was 60.8%, 57.2% and 34.3%, respectively). Continuous application of BPC 157 (in chronic acetate induced gastric ulcer) could accelerate rebuilding of glandular epithelium and formation of granulation tissue (P<0.05 at 200 ng/kg and P<0.01 at 400 ng/kg and 800 ng/kg vs excipient or saline control). Both im and ig administered gastric pentadecapeptide BPC 157 can apparently ameliorate acute gastric ulcer in rats and antagonize the protracted effect of acetate challenge on chronic ulcer. The effect of im administration of BPC 157 is better than that of ig, and the effective dosage of the former is lower than that of the latter.
M. Mergler R. Tanner J. Gosteli P. Grogg
The synthesis of a new polymeric support for the preparation of fully protected peptide fragments by the Fmoc/t-butyl method is described. Data for coupling yields and racemization data are given. Cleavage from the resin is performed by very mild acidolysis.1
Paul Lloyd-Williams Gemma Jou
Fernando Albericio
Ernest Giralt
The use of two different allylic “handles” has been investigated in the solid-phase synthesis of protected peptides. Very high yields for the cleavage of peptides from the resin, under mild conditions which preserve side-chain protecting groups can be achieved by carrying out the cleavage reaction in 2:2:1 THF/DMSO/0.5 M HCl, using morpholine as nucleophile and Pd(Ph3P)4 as catalyst.
Amelie Eriksson Karlström
Anders Undén
The β-3-methylpent-3-yl ester of Fmoc aspartic acid, Fmoc-Asp(OMpe)-OH, is presented as a new protecting group for aspartic acid which provides good protection against base-catalyzed aspartimide formation in Fmoc solid phase peptide synthesis.
Alexander Mitchell Stephen B. H. Kent Martin Engelhard R. B. J. Merrifield
The preferred route to the aminoacylated 4-(oxymethyl)phenylacetamidomethyl-resin (-0CH2-Pam-resin) in- volves the condensation of a Boc-aminoacyl-4-(oxymethyl)phenylacetic acid (Boc = tert -butyloxycarbonyl) with aminomethyl-resin. Aminomethyl-resin was synthesized by direct amidoalkylation of polystyrene resin to give the phthalimidomethyl-resin. The extent of reaction was monitored by IR, allowing the reaction to be stopped at any chosen level of substitution. Hydrazinolysis gave aminomethyl-resin. The Boc-amino acid was converted in solution to a substituted benzyl ester by reaction with 4-(bromomethyl)phenylacetic acid phenacyl ester. Zinc-acetic acid reduction removed the phenacyl group to give the Boc-aminoacyl-4-(oxymethyl)phenylacetic acid, which was cou- pled to aminomethyl-resin with DCC. The benzyl ester bond of the resulting aminoacyl-OCH2-Pam-resins was ap- proximately 100-fold more stable in refluxing trifluoroacetic acid than the aminoacyl-0CH2-resin. Comparison with a solution analogue showed that this was due to the inductive effect of the p-acetamidomethyl group. Cleavage yields (HF-anisole, 9:l v/v, 30 min, 0 "C) were 82-100% for the aminoacyl- and peptidyl-OCH2-Pam-resins exam- ined. The aminoacyl-OCH2-Pam-resins showed resistance to primary amine nucleophiles similar to that of the ami- noacyl-OCH2-resin. No racemization (
R. B. J. Merrifield
A new approach to the chemical synthesis of polypeptides was investigated. It involved the stepwise addition of protected amino acids to a growing peptide chain which was bound by a covalent bond to a solid resin particle. This provided a procedure whereby reagents and by-products were removed by filtration, and the recrystallization of intermediates was eliminated. The advantages of the new method were speed and simplicity of operation. The feasibility of the idea was demonstrated by the synthesis of the model tetrapeptide L-leucyl-L-alanylglycyl-L-valine. The peptide was identical with a sample prepared by the standard p-nitrophenyl ester procedure.
Yan Yang William V. Sweeney
Klaus Schneider
James P. Tam
Aspartimide and its piperidine adduct formed between -Asp-Asn- has been found during an Fmoc-based synthesis of an EGF-like domain in a blood coagulation factor. Model studies with seven susceptible -Asp-X- pentapeptides show that -Asp(Ot-Bu)-Asn(Trt)- and -Asp(Ot-Bu)-Gly- are the most problematic sequences.
Predrag Sikiric Marijan Petek Rudolf Rucman
Irsat Karakas
The possibility that the stomach, affected by general stress, might initiate a counter-response has not until recently been considered in theories of stress. We suggest that the stomach, as the most sensitive part of the gastrointestinal tract and the largest neuroendocrine organ in the body, is crucial for the initiation of a full stress response against all noxious stress pathology. The end result would be a strong protection of all organs invaded by ‘stress’. Consistent with this assumption, this coping response is best explained in terms of ‘organoprotection’. Endogenous organoprotectors (eg prostaglandins, somatostatin, dopamine) are proposed as mediators. Such an endogenous counteraction could even be afforded by their suitable application. A new gastric juice peptide, Mr 40 000, named BPC, was recently isolated. Herein, a 15 amino acid fragment (BPC 157), thought to be essential for its activity, has been fully characterized and investigated. As has been demonstrated for many organoprotective agents using different models of various tissue lesions, despite the poorly understood final mechanism, practically all organ systems appear to benefit from BPC activity. These effects have been achieved in many species using very low dosages (mostly μg and ng/kg range) after ip, ig, and intramucosal (local) application. The effect was apparent already after one application. Long lasting activity was also demonstrated. BPC was highly effective when applied simultaneously with noxious agents or in already pathological, as well as chronical, conditions. Therefore, it seems that BPC treatment does not share any of the so far known limitations for ‘conventional organoprotectors’. No influence on different basal parameters and no toxicity were observed. These findings provide a breakthrough in stress theory, BPC, as a possible endogenous free radical scavenger and organoprotection mediator, could be a useful prototype of a new class of drugs, organoprotective agents.
Predrag Sikiric Marijan Petek Rudolf Rucman
Medina Duvnjak
To elucidate any mechanism of a body protecting effect the observed events should be investigated also by the way of their modulations induced by ablation of particular organs. For Body Protection Compound (BPC), a newly partially characterized gastric juice peptide, the gastroprotection has largely been studied in basal and modified conditions of 48 h-restraint stress. Ablations or sham operations have been performed before restraint as follows: 60 min vagotomy, 24 h ovaria, testes, spleen, 48 h medulla of adrenal glands, 40 days thyroid + parathyroid glands. BPC (10 micrograms/kg) or saline (5 ml/kg) have been regularly applied (after surgery, 1 h before restraint) intraperitoneally. The group subjected to thyroparathyroidectomy received also once-daily BPC/saline treatment. A very strong gastroprotective effect in basal conditions has been modulated by ovariectomy and demedullation (abolishment), thyroparathyroidectomy (decrease), and no change occurred in case of vagotomy, splenectomy or orchidectomy. Sham operated rats did not differ from corresponding controls. Thus, seeing from point of view a wide range of organoprotective effects of BPC (intestinum, kidney, liver, pancreas, inflammation, diabetes mellitus, delayed type of hypersensitivity), the gastroprotection has been supposed a) to be of crucial pattern in the general concept of organo-protection and b) to be responsible for the mediation of the suggested "stomach stress organoprotective response". Therefore, the obtained modulations suggest a complex and specifical, sex-related action of the overall beneficial effects of BPC.
Virender K. Sarin Stephen B. H. Kent
James P. Tam R B Merrifield
A rapid and sensitive method for the quantitative determination of free amino groups during solid-phase peptide synthesis has been developed. The technique involves the reaction of the free amine with ninhydin under carefully controlled conditions and the determination of the resulting chromophore in solution at 570 nm. All of the blue chromophore of the ninhydrin reaction with primary amines is found in solution and the beads of the polystyrene support are colorless. An ion-exchange mechanism for the formation of blue beads by previous methods is proposed. The technique is useful for measuring the total number of peptide chains on the resin and, especially, for monitoring the progress of the coupling reaction. It is possible to determine when the formation of a peptide bond is 99.9% complete.
Stephan A. Gaehde Gary R. Matsueda
N-tert.-butoxycarbonyl-aminomethyl( alpha-phenyl)phenoxyacetic acid was synthesized and found to be suitable for use as a handle in the solid-phase synthesis of peptide alpha-carboxamides. This handle was prepared with an 82% yield when N-tert.-butoxycarbonyl-( rho-hydroxy)benzhydrylamine was treated with excess sodium iodoacetate under alkaline conditions. In stability studies the linkage between the C-terminal amino acid and the handle was found to be resistant to acidolysis in 50% TFA/CH2Cl2 (less than 1% loss after 10h). Upon treatment for 30 min with HF:anisole(9:1) at 0 degrees, 92% cleavage of glycinamide from Gly-handle-resin was obtained. In a test synthesis of a peptide alpha-carboxamide, pyroglutamylhistidylprolinamide was synthesized in 83% yield. Two other handles, tert.-butoxycarbonyl-aminomethylphenoxyacetic acid and N-tert.-butoxycarbonyl-aminomethylphenyloxymethylphenoxyacetic acid, were also synthesized but found to be unsuitable for carboxamide synthesis under the same conditions of solid-phase synthesis.
Kun-hwa Hsieh Margaret M. Demaine S Gurusidaiah
Side reactions in peptide synthesis indicate steps needing improvement as well as opportunities for structural diversification in combinatorial design. Among the side reactions observed in this study, transesterification of Boc-Glu(OBzl) occurred in TMAH-catalyzed resin attachment, leading to Boc-DKKREE(OMe) in solid-phase synthesis of Boc-DKKREE. Acetylation of Boc-Arg(NO2)-resin occurred during resin capping with Ac2O/Et3N, leading to GPR (Ac) in GPR synthesis. His- and Lys-modification occurred during GHRPLDKKREE cleavage from resin by Pd(OAc)2-catalyzed hydrogenation in DMF. To verify these side reactions, model experiments were performed, which indicated rapid transesterification of Boc-Glu(OBzl) in methyl, isopropyl, or tert-butyl alcohol into the corresponding ester by TMAH, but studies of acetylation showed that both Boc-Arg(NO2) and Boc-Arg(Tos) were stable to Ac-Im treatment, but were modified by Ac2O/Et3N. Since transfer hydrogenation of Boc-His(Bzl) and Boc-Lys(Z) in HCOOH or ammonium formate did not generate the formylated side-products of catalytic hydrogenation, DMF and not its decomposed product, HCOOH, appeared involved in side-chain modification. Elimination of the side reactions, by using Cs-derived Boc-Glu(OBzl)-resin for peptide synthesis and catalytic hydrogenation in NMP-HOPr for peptide cleavage, increased the GHRPLDKKREE yield by 1/3. On the other hand, the side reactions provided modified peptides, whose bioassays revealed different importance of the modified side-chains.
Predrag Sikiric Darko Mikus
Sven Seiwerth
Anton Marović
A superior effectiveness in various lesion assays was noted for the novel pentadecapeptide BPC 157, originated from human gastric juice protein (BPC) and claimed to be a cytoprotective agent. From this viewpoint, as a previously untreated experimental improvement to create an acid-free environmental for cytoprotection studies, total gastrectomy was done 24 hr before the ulcerogenic procedure. In the absence of stomach and gastric acid, the damaging effects of cysteamine (400 mg/kg subcutaneously, death 24 hr thereafter), to date thought to be an acid-related duodenal ulcerogen, and the BPC 157 cytoprotective effect (10 microg or 10 ng/kg intraperitoneally) were further challenged. BPC 157 was compared with reference agents [cimetidine (50), ranitidine (10), omeprazole (10), bromocriptine (10) and atropine (10) (mg/kg intraperitoneally, 1 hr before cysteamine] known to be also cytoprotective. In naive rats, with intact stomach, all of them showed a strong beneficial effect. Interestingly, in gastrectomized animals, the application of BPC 157 or the reference agents before cysteamine significantly prevented the otherwise severe duodenal lesion development noted in the control gastrectomized cysteamine rats. In groups without cysteamine, no lesions were noted (laparotomy, gastrectomy only, 24 or 48 hr postsurgical period), nor was lesion potentiation seen in cysteamine-treated laparotomized animals. In summary, these findings--equal damaging effect of cysteamine and equal protection of pentadecapeptide BPC 157 and reference agents in gastrectomized and rats with intact stomach--seem to be particularly relevant for a cytoprotective viewpoint. Without a stomach, the cysteamine damaging effect was convincingly defined as an essential gastric acid-independent injury (analogous to ethanol gastric lesions). Likewise, a high "cytoprotective capacity," apparently acid independent, common for all tested agents (novel pentadecapeptide BPC 157, cimetidine, ranitidine, omeprazole and atropine) could be clearly stressed.
M. M. Mergler Fritz Dick B Sax
Thomas Vorherr
A variety of Asp beta-carboxy protecting groups, Hmb backbone protection and a range of Fmoc cleavage protocols have been employed in syntheses of the model hexapeptide H-VKDGYI-OH to investigate the aspartimide problem in more detail. The extent of formation of aspartimide and aspartimide-related by-products was determined by RP-HPLC. This study included three new Fmoc-Asp-OH derivatives: the beta-(4-pyridyl-diphenylmethyl) and beta-(9-phenyl-fluoren-9-yl) esters and also the orthoester Fmoc-beta-(4-methyl-2,6,7-trioxabicyclo[2.2.2]-oct-1-yl)-alanine. 3-Methylpent-3-yl protection of the Asp side chain resulted in significant improvements with respect to aspartimide formation. Complete suppression was achieved using the combination OtBu side chain protection and Hmb backbone protection for the preceding Gly residue.
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