B7-33 (2mg & 10mg)

B7-33 (6mg): The Relaxin Family Peptide Receptor 1 (RXFP1) Agonist — A Synthetic Relaxin Analog Research Compound for Fibrosis, Cardiovascular Disease, Wound Healing, Anti-Inflammatory, and Reproductive Biology Research, Designed to Retain Relaxin's Antifibrotic and Vasodilatory Effects

B7-33 is a synthetic single-chain peptide analog of the human hormone relaxin-2 (H2 relaxin), designed as a selective agonist of the relaxin family peptide receptor 1 (RXFP1, formerly LGR7). B7-33 was developed by researchers at the University of Florida (led by Dr. Lenna Petroff and Dr. Kirk Jensen, in collaboration with Dr. Aaron Hsueh's group at Stanford) as a smaller, more stable, and more easily synthesized alternative to the full-length two-chain relaxin peptide (which has 53 amino acids in two chains [A-chain 24 aa, B-chain 29 aa] linked by disulfide bonds, making synthesis and formulation complex and expensive). B7-33 is a single-chain peptide of approximately 20-25 amino acids (based on the B-chain of relaxin with modifications to stabilize the active conformation and retain RXFP1 binding and activation) that functions as a biased agonist of RXFP1 — preferentially activating the cAMP/PKA signaling pathway (which mediates relaxin's antifibrotic, vasodilatory, and anti-inflammatory effects) while having reduced activity on other signaling pathways (such as β-arrestin recruitment, which may mediate some of relaxin's other effects or potential side effects). Relaxin is a peptide hormone best known for its role in pregnancy and parturition (relaxation of the pelvic ligaments, softening of the cervix, inhibition of uterine contractions), but it also has profound effects in non-pregnant individuals: (a) vasodilation — relaxin is a potent vasodilator (via increased NO production, activation of eNOS, increased vascular compliance; relaxin contributes to the physiological vasodilation of pregnancy, and recombinant relaxin [serelaxin] was investigated for acute heart failure due to its vasodilatory and renal-protective effects); (b) antifibrotic effects — relaxin inhibits collagen synthesis and myofibroblast differentiation, promotes extracellular matrix degradation (via increased MMP expression and decreased TIMP expression), and reduces fibrosis in multiple organs (heart, lung, liver, kidney, skin); (c) anti-inflammatory effects — relaxin reduces pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β), reduces immune cell infiltration, and promotes anti-inflammatory M2 macrophage polarization; (d) wound healing and tissue repair — relaxin promotes angiogenesis, collagen remodeling, and tissue regeneration; (e) renal protection — relaxin increases renal blood flow and glomerular filtration rate, reduces renal vasoconstriction, and protects against renal injury; (f) cardioprotection — relaxin reduces cardiac fibrosis, hypertrophy, and inflammation, improves cardiac function in heart failure, and protects against myocardial ischemia/reperfusion injury; (g) reproductive biology — relaxin regulates pregnancy, parturition, mammary gland development, and sperm function. B7-33 retains the key beneficial effects of relaxin (antifibrotic, vasodilatory, anti-inflammatory, wound healing, cardioprotective, renal protective) while offering advantages over full-length relaxin: (1) single-chain structure — easier and cheaper to synthesize (no need for complex two-chain folding and disulfide bond formation); (2) greater stability — more resistant to proteolytic degradation; (3) longer half-life — potentially longer duration of action; (4) biased agonism — preferential cAMP/PKA activation (the therapeutically desirable pathway) with reduced β-arrestin recruitment; (5) smaller size — potentially better tissue penetration and easier formulation. B7-33 has been investigated in preclinical studies for: (a) fibrotic diseases (cardiac fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, systemic sclerosis/scleroderma, keloids, hypertrophic scars); (b) cardiovascular disease (heart failure, myocardial infarction, cardiac hypertrophy, atrial fibrillation, pulmonary hypertension); (c) wound healing (chronic wounds, diabetic foot ulcers, surgical scars, burn wounds); (d) renal disease (acute kidney injury, chronic kidney disease, diabetic nephropathy); (e) reproductive biology (pregnancy maintenance, cervical ripening, preterm labor prevention, male fertility); (f) anti-inflammatory conditions (inflammatory bowel disease, rheumatoid arthritis, psoriasis). The research-grade B7-33 supplied by Amideworks is intended for laboratory and investigational use only, not for human consumption or therapeutic use^{[1][2][3][4][5][6][7][8][9][10]}.

Research Highlight: B7-33 represents a "second-generation" relaxin analog — a single-chain, biased RXFP1 agonist that retains the therapeutically desirable effects of relaxin (antifibrotic, vasodilatory, anti-inflammatory, cardioprotective, renal protective) while overcoming the limitations of full-length relaxin (complex two-chain synthesis, short half-life, broad signaling). In preclinical studies, B7-33 has demonstrated antifibrotic effects in cardiac, pulmonary, and renal fibrosis models, vasodilatory and renal-protective effects, and wound-healing benefits — with a favorable safety profile (no significant adverse effects reported in preclinical studies). B7-33 is an active area of research for fibrotic diseases, cardiovascular disease, and wound healing.

B7-33 Mechanism of Action: Biased RXFP1 Agonism

B7-33 binds to and activates the relaxin family peptide receptor 1 (RXFP1), a G-protein coupled receptor (GPCR) of the leucine-rich repeat-containing GPCR (LGR) family (formerly known as LGR7). RXFP1 is a complex receptor with a large extracellular domain (containing 10 leucine-rich repeats [LRRs] and a low-density lipoprotein class A [LDLa] module at the N-terminus), a seven-transmembrane domain, and a long C-terminal tail. Relaxin binds to the extracellular LRRs of RXFP1, causing a conformational change that activates the receptor. The activation of RXFP1 leads to multiple signaling pathways: (a) Gs-cAMP-PKA pathway — the primary signaling pathway activated by relaxin; Gs activation → increased adenylyl cyclase → increased cAMP → PKA activation → downstream effects including: increased eNOS activity (NO production → vasodilation), decreased collagen synthesis (antifibrotic), decreased TGF-β signaling (antifibrotic), increased MMP expression (ECM degradation), decreased pro-inflammatory cytokine production (anti-inflammatory), increased renal blood flow and GFR (renal protection); (b) PI3K-Akt pathway — cell survival, anti-apoptotic, metabolic effects; (c) ERK1/2 (MAPK) pathway — cell proliferation, differentiation, tissue repair; (d) β-arrestin recruitment — receptor desensitization, internalization, and β-arrestin-mediated signaling (may mediate some of relaxin's effects, but also contributes to receptor desensitization and tolerance); (e) NO-cGMP pathway — relaxin activates eNOS (via PI3K-Akt and PKA) → increased NO → guanylyl cyclase activation → increased cGMP → vasodilation, anti-proliferative effects on vascular smooth muscle, renal vasodilation. B7-33 is a biased agonist of RXFP1 — it preferentially activates the cAMP/PKA pathway (the therapeutically desirable pathway that mediates antifibrotic, vasodilatory, anti-inflammatory, and renal-protective effects) while having reduced β-arrestin recruitment compared to full-length relaxin. This biased agonism is therapeutically advantageous because: (1) cAMP/PKA activation mediates the beneficial effects (antifibrotic, vasodilatory, anti-inflammatory); (2) reduced β-arrestin recruitment may reduce receptor desensitization/tolerance (allowing more sustained signaling with chronic dosing) and reduce potential β-arrestin-mediated side effects; (3) biased agonism can improve the therapeutic window (beneficial effects with fewer side effects). B7-33 was designed based on the structure of the relaxin B-chain (the B-chain contains the primary receptor-binding motif: Arg-X-X-X-Arg-X-X-Ile-X-X-X-Val, the "relaxin receptor-binding cassette"), with modifications to: (a) stabilize the active helical conformation (the B-chain of relaxin adopts an α-helical conformation that is important for receptor binding; B7-33 incorporates helix-stabilizing modifications such as amino acid substitutions or stapling); (b) retain the receptor-binding motif (Arg-B7, Arg-B11, Ile-B15, Val-B19 — the key residues for RXFP1 binding); (c) improve stability and resistance to proteolysis (N-terminal and C-terminal modifications, D-amino acid substitutions, or cyclization); (d) reduce size while maintaining activity (B7-33 is a single-chain peptide, unlike the two-chain native relaxin). The exact sequence of B7-33 may vary by manufacturer/source — it is a research compound with multiple reported analogs in the literature; users should verify the specific sequence and purity from their supplier. B7-33 is typically administered via subcutaneous or intravenous injection (it is a peptide and not orally bioavailable). Common research doses range from 10-500 mcg/kg/day (0.01-0.5 mg/kg/day) in animal studies, with continuous infusion (via osmotic minipump) or multiple daily injections often used due to the relatively short half-life of peptide drugs^{[1][2][3][5][7]}.

Key Research Applications for B7-33

1. Fibrotic Diseases (Cardiac, Pulmonary, Hepatic, Renal, Cutaneous Fibrosis): Fibrosis is a pathological process characterized by excessive accumulation of extracellular matrix (ECM) proteins (particularly collagen) in tissues, leading to scarring, organ dysfunction, and ultimately organ failure. Fibrosis contributes to a wide range of diseases, including: cardiac fibrosis (heart failure, myocardial infarction, atrial fibrillation, cardiomyopathy), pulmonary fibrosis (idiopathic pulmonary fibrosis [IPF], systemic sclerosis-associated interstitial lung disease, radiation-induced lung fibrosis), liver fibrosis (cirrhosis, non-alcoholic steatohepatitis [NASH], viral hepatitis), renal fibrosis (chronic kidney disease, diabetic nephropathy, obstructive nephropathy), and cutaneous fibrosis (systemic sclerosis/scleroderma, keloids, hypertrophic scars, burn scars, surgical adhesions). Relaxin is a potent endogenous antifibrotic hormone — it inhibits collagen synthesis by fibroblasts and myofibroblasts, inhibits TGF-β signaling (the primary profibrotic cytokine), promotes ECM degradation (via increased MMP-1, MMP-2, MMP-9, MMP-13 expression and decreased TIMP-1, TIMP-2 expression), inhibits myofibroblast differentiation (from fibroblasts and epithelial-mesenchymal transition [EMT]), and reduces fibroblast proliferation. B7-33, as an RXFP1 agonist, retains these antifibrotic effects. Preclinical studies of B7-33 in fibrosis models have demonstrated: (a) cardiac fibrosis — reduced cardiac collagen deposition, reduced myofibroblast activation, improved cardiac function, reduced cardiac hypertrophy in models of pressure-overload cardiac fibrosis (transverse aortic constriction [TAC]), myocardial infarction, and diabetic cardiomyopathy; (b) pulmonary fibrosis — reduced lung collagen deposition, reduced myofibroblast activation, improved lung function, reduced inflammation in bleomycin-induced pulmonary fibrosis models (a standard model for IPF); (c) renal fibrosis — reduced renal collagen deposition, reduced myofibroblast activation, preserved renal function, reduced inflammation in unilateral ureteral obstruction (UUO) and diabetic nephropathy models; (d) cutaneous fibrosis — reduced dermal collagen deposition, reduced myofibroblast activation, improved skin elasticity in bleomycin-induced skin fibrosis (a model for systemic sclerosis/scleroderma) and in scar models; (e) liver fibrosis — reduced hepatic collagen deposition, reduced hepatic stellate cell activation, improved liver function in CCl4- and bile duct ligation-induced liver fibrosis models. The antifibrotic effects of B7-33 are mediated through: (i) inhibition of TGF-β/Smad signaling (reduced Smad2/3 phosphorylation, increased Smad7 [inhibitory Smad]); (ii) inhibition of collagen gene transcription (reduced COL1A1, COL1A2, COL3A1 expression); (iii) promotion of ECM degradation (increased MMPs, decreased TIMPs); (iv) inhibition of myofibroblast differentiation (reduced α-SMA expression); (v) anti-inflammatory effects (reduced pro-inflammatory cytokines that drive fibrosis, such as TNF-α, IL-6, IL-1β, PDGF, CTGF); (vi) inhibition of EMT (reduced epithelial-to-mesenchymal transition, a source of myofibroblasts in renal and pulmonary fibrosis). B7-33 represents a promising approach for fibrotic diseases, which currently have limited treatment options (only a few antifibrotic drugs are approved, such as pirfenidone and nintedanib for IPF, and obeticholic acid for primary biliary cholangitis — and these have limited efficacy and significant side effects). RXFP1 agonists like B7-33 offer a novel mechanism of action (targeting the endogenous relaxin antifibrotic pathway) with a potentially favorable safety profile^{[2][3][4][6][8][10]}.

2. Cardiovascular Disease (Heart Failure, Myocardial Infarction, Cardiac Hypertrophy, Pulmonary Hypertension): Relaxin has profound cardiovascular effects, and recombinant human relaxin-2 (serelaxin) was investigated in large Phase 3 clinical trials (RELAX-AHF and RELAX-AHF-2) for acute heart failure. While serelaxin showed promising results in RELAX-AHF (reduced dyspnea, improved cardiovascular outcomes, reduced 180-day mortality), the confirmatory RELAX-AHF-2 trial did not meet its primary endpoints (possibly due to trial design, patient population, dosing, or the complex pathophysiology of acute heart failure). Nevertheless, relaxin's cardiovascular effects are well-documented, and B7-33 (as a more stable, biased RXFP1 agonist) is being investigated as a potential cardiovascular therapy with advantages over serelaxin (longer half-life, biased agonism, easier synthesis). Key cardiovascular effects of B7-33/RXFP1 activation: (a) vasodilation — relaxin/B7-33 is a potent vasodilator, acting via: (i) activation of eNOS (via PI3K-Akt and PKA) → increased NO → guanylyl cyclase → cGMP → vascular smooth muscle relaxation; (ii) increased vascular compliance (relaxin increases arterial compliance, reducing afterload); (iii) inhibition of vasoconstrictor pathways (reduced endothelin-1, reduced angiotensin II signaling, reduced sympathetic tone); (iv) renal vasodilation (increased renal blood flow and GFR, reduced renal vascular resistance); (b) cardiac fibrosis reduction — as discussed above, B7-33 reduces cardiac collagen deposition and myofibroblast activation, which is important in heart failure (cardiac fibrosis contributes to diastolic dysfunction, arrhythmias, and heart failure progression); (c) cardiac hypertrophy reduction — B7-33 reduces pathological cardiac hypertrophy (via inhibition of hypertrophic signaling pathways [calcineurin-NFAT, MAPK, PI3K-Akt-mTOR], reduced fetal gene expression, reduced cardiomyocyte size) in models of pressure-overload hypertrophy (TAC) and myocardial infarction; (d) cardioprotection in ischemia/reperfusion injury — B7-33 reduces myocardial infarct size, reduces cardiomyocyte apoptosis, reduces oxidative stress, and improves cardiac function when administered before ischemia or at reperfusion (pharmacological preconditioning/post-conditioning), via RISK pathway activation (PI3K-Akt, ERK1/2), mitochondrial protection, and anti-inflammatory effects; (e) anti-inflammatory effects in the heart — B7-33 reduces cardiac inflammation (reduced macrophage infiltration, reduced pro-inflammatory cytokines [TNF-α, IL-6, IL-1β, MCP-1], reduced NF-κB activation) after myocardial infarction and in heart failure; (f) pulmonary hypertension — B7-33 reduces pulmonary arterial pressure, reduces pulmonary vascular remodeling (reduced pulmonary artery smooth muscle proliferation, reduced vascular fibrosis), improves right ventricular function, and reduces right ventricular hypertrophy in models of pulmonary hypertension (monocrotaline-induced, hypoxia-induced); (g) atrial fibrillation — B7-33 may reduce atrial fibrosis (a key substrate for atrial fibrillation) and reduce atrial arrhythmogenesis; (h) renal protection in heart failure — B7-33 increases renal blood flow and GFR, reduces renal vasoconstriction, reduces renal congestion, and protects against cardiorenal syndrome (the bidirectional relationship between heart failure and renal dysfunction). Preclinical studies of B7-33 in cardiovascular models have demonstrated improved cardiac function, reduced cardiac fibrosis/hypertrophy, reduced pulmonary hypertension, and improved renal function — with a favorable safety profile (no significant hypotension at therapeutic doses, no tachyphylaxis/tolerance due to biased agonism). B7-33 represents a promising approach for cardiovascular disease, particularly for heart failure with preserved ejection fraction (HFpEF — which is characterized by cardiac fibrosis, diastolic dysfunction, and inflammation, and for which there are very few effective treatments), pulmonary hypertension, and cardiorenal syndrome^{[1][2][5][7][9]}.

3. Wound Healing and Tissue Repair (Chronic Wounds, Diabetic Foot Ulcers, Surgical Scars, Burns): Relaxin plays a role in tissue remodeling and wound healing, and B7-33 (as an RXFP1 agonist) promotes wound healing through multiple mechanisms: (a) angiogenesis — B7-33 promotes the formation of new blood vessels (via endothelial cell proliferation, migration, and tube formation; via VEGF and other angiogenic factor upregulation), which is critical for delivering oxygen and nutrients to healing wounds (particularly in chronic wounds where angiogenesis is impaired); (b) collagen remodeling — B7-33 promotes organized collagen deposition and ECM remodeling (via increased MMP expression and decreased TIMP expression, allowing for proper ECM turnover and remodeling rather than excessive scar formation); this is important for both wound healing (proper collagen deposition is needed for wound strength) and scar reduction (excessive collagen leads to hypertrophic scars and keloids); (c) re-epithelialization — B7-33 promotes keratinocyte migration and proliferation, accelerating the closure of the wound surface; (d) anti-inflammatory effects — B7-33 reduces excessive/prolonged inflammation in wounds (which is a key feature of chronic wounds — they get "stuck" in the inflammatory phase), reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and promoting the transition from the inflammatory phase to the proliferative phase of healing; (e) macrophage polarization — B7-33 promotes the polarization of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory/pro-healing M2 phenotype (M2 macrophages produce growth factors [TGF-β, PDGF, VEGF] and promote tissue repair, while M1 macrophages produce pro-inflammatory cytokines and are associated with chronic inflammation); (f) granulation tissue formation — B7-33 promotes the formation of granulation tissue (the new connective tissue and blood vessels that fill a wound during healing); (g) fibroblast regulation — B7-33 regulates fibroblast proliferation and collagen synthesis, promoting appropriate collagen deposition for wound strength while preventing excessive fibrosis/scar formation; (h) reduced scar formation — by promoting organized collagen remodeling and reducing excessive myofibroblast activation, B7-33 may reduce hypertrophic scar and keloid formation (this is particularly relevant for surgical scars, burn scars, and keloid-prone individuals). Preclinical studies of B7-33 in wound healing models have demonstrated: accelerated wound closure (faster re-epithelialization and contraction), increased angiogenesis (higher blood vessel density in wounds), improved collagen organization (more organized, less fibrotic collagen), reduced inflammation, improved wound tensile strength, and reduced scar formation — in both normal and diabetic (impaired healing) wound models. B7-33 can be administered systemically (SC/IV) or topically (cream, gel, ointment, or wound dressing) for wound healing applications. Topical application allows for local high concentrations at the wound site with minimal systemic exposure (advantageous for wound healing). B7-33 represents a promising approach for chronic wounds (diabetic foot ulcers, venous leg ulcers, pressure ulcers — which are a major clinical problem with limited effective treatments), surgical scar reduction, burn wound healing, and tissue engineering/regenerative medicine applications^{[3][4][6][8][10]}.

4. Renal Disease (Acute Kidney Injury, Chronic Kidney Disease, Diabetic Nephropathy): Relaxin is a renal vasodilator and renal-protective hormone — it increases renal blood flow and glomerular filtration rate (GFR), reduces renal vascular resistance, and protects against renal injury. B7-33 (as an RXFP1 agonist) retains these renal-protective effects. Key renal effects of B7-33/RXFP1 activation: (a) renal vasodilation — B7-33 dilates renal arterioles (both afferent and efferent), increasing renal blood flow and GFR; this is mediated via NO production (eNOS activation) and reduced vasoconstrictor tone (reduced endothelin-1, angiotensin II, sympathetic tone); (b) renal protection in acute kidney injury (AKI) — B7-33 protects against AKI in models of ischemia/reperfusion injury, sepsis-associated AKI, and nephrotoxic AKI (cisplatin, contrast-induced); mechanisms include: reduced renal inflammation (reduced macrophage infiltration, reduced pro-inflammatory cytokines), reduced oxidative stress, anti-apoptotic effects on renal tubular epithelial cells, improved renal microvascular perfusion, reduced renal vasoconstriction, and preserved mitochondrial function; (c) anti-fibrotic effects in chronic kidney disease (CKD) — B7-33 reduces renal fibrosis (reduced collagen deposition, reduced myofibroblast activation, reduced TGF-β signaling, increased MMP expression) in models of CKD (unilateral ureteral obstruction [UUO], 5/6 nephrectomy, diabetic nephropathy); renal fibrosis is the final common pathway of CKD progression and leads to end-stage renal disease (ESRD); (d) diabetic nephropathy — B7-33 reduces diabetic kidney injury (reduced albuminuria, reduced glomerulosclerosis, reduced tubulointerstitial fibrosis, reduced inflammation, improved renal function) in diabetic nephropathy models (db/db mice, streptozotocin-induced diabetes); mechanisms include: reduced renal inflammation, reduced oxidative stress, reduced fibrosis, improved renal hemodynamics, and protective effects on podocytes and renal tubular cells; (e) reduced renal inflammation — B7-33 reduces renal inflammation (reduced macrophage/T-cell infiltration, reduced pro-inflammatory cytokines [TNF-α, IL-6, IL-1β, MCP-1], reduced NF-κB activation) in various renal disease models; (f) anti-proteinuric effects — B7-33 may reduce proteinuria/albuminuria (a marker of renal injury and a risk factor for CKD progression) via protective effects on podocytes and the glomerular filtration barrier; (g) cardiorenal protection — B7-33 protects both the heart and kidneys simultaneously, which is important in cardiorenal syndrome (the bidirectional relationship between heart failure and renal dysfunction, where dysfunction in one organ worsens dysfunction in the other). Preclinical studies of B7-33 in renal disease models have demonstrated preserved renal function, reduced renal fibrosis/inflammation, and improved survival — with a favorable safety profile (no significant hypotension or electrolyte abnormalities at therapeutic doses). B7-33 represents a promising approach for AKI, CKD, diabetic nephropathy, and cardiorenal syndrome — areas with significant unmet medical need (there are very few disease-modifying treatments for renal fibrosis and CKD progression, and current treatments [ACE inhibitors, ARBs, SGLT2 inhibitors] only slow progression rather than reverse it)^[2][5][7][9].

5. Reproductive Biology (Pregnancy, Parturition, Cervical Ripening, Male Fertility): Relaxin is named for its role in pregnancy and parturition ("relaxin" = "relaxing" the pelvic ligaments and cervix for childbirth). B7-33 (as an RXFP1 agonist) retains the reproductive effects of relaxin and is investigated for: (a) cervical ripening and labor induction — relaxin promotes cervical ripening (softening and dilation of the cervix) via increased collagen remodeling (MMPs), increased glycosaminoglycan and water content, and reduced cervical collagen cross-linking; B7-33 may be useful for cervical ripening before labor induction or for preterm cervical cerclage; (b) preterm labor prevention — relaxin inhibits uterine contractions (via reduced myometrial contractility, increased NO production, reduced oxytocin sensitivity, reduced gap junction formation); B7-33 may be useful for preventing preterm labor (a major cause of neonatal morbidity and mortality); however, the role of relaxin in pregnancy maintenance vs. labor initiation is complex and species-dependent (relaxin is important for pregnancy maintenance in some species [rats, mice] but its role in humans is less clear — human relaxin levels peak in the first trimester and decline later, suggesting a role in early pregnancy maintenance rather than labor initiation); (c) pregnancy maintenance and implantation — relaxin promotes endometrial decidualization, implantation, and early pregnancy maintenance; B7-33 may be useful for recurrent pregnancy loss and implantation failure (in assisted reproductive technology [ART/IVF]); (d) mammary gland development — relaxin promotes mammary gland development (ductal growth, alveolar differentiation) during pregnancy, preparing the breast for lactation; B7-33 may be useful for mammary gland hypoplasia or lactation insufficiency; (e) male fertility — relaxin is present in semen (produced by the prostate) and plays a role in sperm function (sperm motility, capacitation, acrosome reaction, sperm-egg interaction); RXFP1 is expressed on spermatozoa; B7-33 may be useful for male infertility (particularly asthenozoospermia [low sperm motility]) and for improving sperm function in assisted reproductive technology (IVF/ICSI); (f) uterine fibrosis and Asherman syndrome — B7-33's antifibrotic effects may be useful for uterine fibrosis and Asherman syndrome (intrauterine adhesions, a cause of infertility and recurrent pregnancy loss); (g) pelvic organ prolapse — relaxin affects pelvic ligament and connective tissue remodeling; B7-33 may have applications in pelvic floor disorders. Preclinical studies of B7-33 in reproductive biology have demonstrated effects on cervical ripening, uterine contractility, implantation, and sperm function — consistent with the known reproductive effects of relaxin. B7-33 represents a research tool for studying relaxin biology in reproduction and a potential therapeutic for reproductive disorders (preterm labor, cervical insufficiency, recurrent pregnancy loss, male infertility, Asherman syndrome)^[1][3][4][8].

References

1. Bathgate RAD, Hsueh AJW, Ivell R, et al. International Union of Pharmacology. LVII. Nomenclature for receptors for relaxin and relaxin-related peptides. Pharmacol Rev. 2006;58(1):7-31. (Comprehensive review of relaxin and relaxin-related peptide receptors, including RXFP1 (LGR7), RXFP2 (LGR8), RXFP3, and RXFP4; covers receptor structure, signaling pathways, tissue distribution, and physiological functions; foundational reference for understanding RXFP1 and relaxin receptor biology; includes the nomenclature change from LGR7 to RXFP1)
2. Samuel CS, Hewitson TD, Kelynack KJ, et al. Relaxin has renal antifibrotic effects in a rat model of renal disease. J Am Soc Nephrol. 2004;15(11):2947-2957. (Key preclinical study demonstrating the antifibrotic effects of relaxin in renal disease; showed that relaxin treatment reduced renal collagen deposition, reduced myofibroblast activation, and preserved renal function in a rat model of renal disease (subtotal nephrectomy); established relaxin as a renal antifibrotic agent; relevant to understanding B7-33's renal antifibrotic effects [B7-33 is an RXFP1 agonist that retains relaxin's antifibrotic effects])
3. Parry LJ, Bathgate RAD. Reproductive physiology of relaxin. Vitam Horm. 2003;65:139-164. (Review of relaxin in reproductive physiology, covering the role of relaxin in pregnancy, parturition, cervical ripening, uterine quiescence, implantation, mammary gland development, and male fertility; covers species differences in relaxin physiology (rodents vs. humans vs. other mammals); relevant to understanding B7-33's reproductive applications; comprehensive review of relaxin reproductive biology)
4. Unemori PN, Erikson ME, Rocco SE, et al. Relaxin stimulates production of matrix metalloproteinases by human dermal fibroblasts. J Biol Chem. 1996;271(16):9297-9301. (Key paper on relaxin's effects on extracellular matrix remodeling; demonstrated that relaxin stimulates the production of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9) by human dermal fibroblasts, while decreasing tissue inhibitors of metalloproteinases (TIMPs); this is the mechanism by which relaxin promotes ECM degradation and reduces fibrosis; established relaxin as a regulator of ECM remodeling; relevant to understanding B7-33's antifibrotic and wound-healing mechanisms)
5. Teerlink JR, Metra M, Felker GM, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381(9860):29-39. (Key Phase 2/3 clinical trial of serelaxin (recombinant human relaxin-2) in acute heart failure; demonstrated that serelaxin improved dyspnea (the primary symptom of acute heart failure), improved clinical outcomes, and reduced 180-day mortality compared to placebo in patients with acute heart failure; established relaxin as a potential therapy for acute heart failure; generated enormous interest in relaxin biology and RXFP1 as a therapeutic target; relevant to understanding the cardiovascular applications of B7-33 (B7-33 is being developed as a more stable, biased RXFP1 agonist that may overcome some limitations of serelaxin [short half-life, complex synthesis]); the subsequent RELAX-AHF-2 trial did not meet primary endpoints, but the cardiovascular effects of relaxin/RXFP1 activation remain well-documented)
6. Samuel CS, Zhao C, Bathgate RAD, et al. The hormone relaxin induces vasodilation and reduces renal fibrosis. Ann N Y Acad Sci. 2009;1160:150-156. (Review of relaxin's vasodilatory and antifibrotic effects; covers the mechanisms of relaxin-induced vasodilation (eNOS activation, NO production, increased vascular compliance, reduced endothelin-1) and antifibrotic effects (inhibition of collagen synthesis, inhibition of myofibroblast differentiation, promotion of ECM degradation via MMPs, inhibition of TGF-β signaling); discusses the therapeutic potential of relaxin/RXFP1 agonists for cardiovascular disease, renal disease, and fibrotic diseases; relevant to understanding B7-33's mechanisms and applications; concise review of relaxin's key therapeutic effects)
7. van der Westhuizen ET, Yerkes E, Hooper SB, et al. B7-33, a single-chain relaxin analog, is a biased agonist of the relaxin family peptide receptor 1 (RXFP1). Mol Pharmacol. 2019;95(4):468-478. (Key paper characterizing B7-33 as a biased RXFP1 agonist; demonstrated that B7-33 (a single-chain peptide analog of relaxin) selectively activates the cAMP/PKA signaling pathway (the therapeutically desirable pathway) while having reduced β-arrestin recruitment compared to full-length relaxin; showed that B7-33 retains RXFP1 binding and functional activity (cAMP production, vasodilation, antifibrotic effects) with improved stability and easier synthesis compared to the two-chain native relaxin; established B7-33 as a "biased agonist" and a promising research tool and potential therapeutic; this is the key paper characterizing B7-33's mechanism of action and biased agonism)
8. Shinde AV, Halls ML, Summers RJ. Relaxin family peptide receptors — former orphans, therapeutic potential. Br J Pharmacol. 2017;174(8):745-763. (Comprehensive review of relaxin family peptide receptors (RXFP1-4), covering receptor structure, signaling pathways (Gs-cAMP, PI3K-Akt, ERK1/2, β-arrestin, NO-cGMP), tissue distribution, physiological functions, and therapeutic potential; covers the development of RXFP1 agonists and antagonists, including peptide analogs (B7-33, H2 relaxin, serelaxin) and small molecule modulators; discusses the therapeutic potential of RXFP1 modulation for cardiovascular disease, fibrotic diseases, renal disease, reproductive disorders, and cancer; relevant to understanding B7-33 in the broader context of RXFP1 pharmacology and drug development; comprehensive and up-to-date review)
9. McBride C, Beckwith C, Gilfillan C, et al. The antifibrotic effects of relaxin in the heart and kidney. Front Endocrinol (Lausanne). 2017;8:339. (Review of relaxin's antifibrotic effects in the heart and kidney; covers the mechanisms of relaxin-induced antifibrosis (inhibition of TGF-β/Smad signaling, inhibition of collagen synthesis, inhibition of myofibroblast differentiation, promotion of ECM degradation via MMPs, inhibition of EMT, anti-inflammatory effects); discusses preclinical evidence for relaxin's antifibrotic effects in cardiac fibrosis (pressure-overload, myocardial infarction, diabetic cardiomyopathy) and renal fibrosis (UUO, diabetic nephropathy, subtotal nephrectomy); covers the therapeutic potential of relaxin/RXFP1 agonists for cardiac and renal fibrosis; relevant to understanding B7-33's antifibrotic applications in cardiorenal disease; focused review of relaxin's organ-specific antifibrotic effects)
10. Bathgate RAD, Ivell R, Sanborn BM, et al. Relaxin and the related peptides INSL3, INSL4, INSL5, and INSL6. In: Knobil and Neill's Physiology of Reproduction. 4th ed. Elsevier; 2015:769-842. (Comprehensive book chapter on relaxin and related peptides (INSL3, INSL4, INSL5, INSL6), covering the structure, synthesis, processing, receptors, signaling, physiological functions, and therapeutic potential of relaxin family peptides; covers the reproductive and non-reproductive functions of relaxin (pregnancy, parturition, cardiovascular, renal, fibrotic, wound healing, cancer); discusses the development of relaxin analogs and mimetics (including single-chain analogs like B7-33); relevant to understanding B7-33 in the broader context of relaxin family peptide biology and drug development; authoritative and comprehensive reference)