Hexa-D-arginine

Hexa-D-arginine is an inhibitor of furin. Sequence: Arg-Arg-Arg-Arg-Arg-Arg-NH2.

In Vitro:Hexa-D-arginine (10 μM) protects against the cytotoxic effects of anthrax toxin in RAW 264.7 cells. The concentrations of Hexa-D-arginine requires to block the cleavage of PA are similar to those required to inhibit toxicity[2].

In Vivo:Administration of hexa-d-arginine to PEA-treated mice significantly improves their survival rate and also decreases circulating levels of tumor necrosis factor alpha[1]. Rats treated with the combination of anthrax toxins and Hexa-D-arginine exhibit a 40% survival rate at 5 h compared with a control group treated solely with anthrax toxin (0% survival rate). Administration of Hexa-D-arginine (1 mg/100 μL) also results in a considerable delay in the onset of anthrax toxemia compared with results of the control group treated solely with anthrax toxin[2].

References:
[1]. Sarac MS, et al. The furin inhibitor hexa-D-arginine blocks the activation of Pseudomonas aeruginosa exotoxin A in vivo. Infect Immun. 2002 Dec;70(12):7136-9. [2]. Sarac MS, et al. Protection against anthrax toxemia by hexa-D-arginine in vitro and in vivo. Infect Immun. 2004 Jan;72(1):602-5.

Protection against anthrax toxemia by hexa-D-arginine in vitro and in vivo.[Pubmed:14688144]

Infect Immun. 2004 Jan;72(1):602-5.

The anthrax toxin protective antigen precursor is activated by proteolytic cleavage by furin or a furin-like protease. We present here data demonstrating that the small stable furin inhibitor Hexa-D-arginine amide delays anthrax toxin-induced toxemia both in cells and in live animals, suggesting that furin inhibition may represent a reasonable avenue for therapeutic intervention in anthrax.

Conjugation of adenosine and hexa-(D-arginine) leads to a nanomolar bisubstrate-analog inhibitor of basophilic protein kinases.[Pubmed:17125267]

J Med Chem. 2006 Nov 30;49(24):7150-9.

Conjugates of oligoarginine peptides with adenine, adenosine, adenosine-5'-carboxylic acid, and 5-isoquinolinesulfonic acid were synthesized and characterized as bisubstrate-analog inhibitors of cAMP-dependent protein kinase. Adenosine and adenine derivatives were connected to the N- or C-terminus of peptides containing four to six L- or D-arginine residues via a linker with a length that had been optimized in structure-activity studies. The orientation of the peptide chain strongly affected the activity of compounds incorporating D-arginines. The biligand inhibitor containing Hidaka's H9 isoquinolinesulfonamide connected to the L-peptide had 65 times higher potency than the corresponding adenosine-containing conjugate, while both types of the conjugate comprising D-peptides had similar low nanomolar activity. Two of the most active adenosine- and H9-peptide conjugates were tested in the panel of 52 different kinases. At 1 microM concentration, both compounds showed strong (more than 95%) inhibition of several basophilic AGC kinases, including pharmaceutically important kinases ROCK II and PKB/Akt.

Hexa-D-arginine treatment increases 7B2*PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype.[Pubmed:22886699]

J Bone Miner Res. 2013 Jan;28(1):56-72.

Inactivating mutations of the "phosphate regulating gene with homologies to endopeptidases on the X chromosome" (PHEX/Phex) underlie disease in patients with X-linked hypophosphatemia (XLH) and the hyp-mouse, a murine homologue of the human disorder. Although increased serum fibroblast growth factor 23 (FGF-23) underlies the HYP phenotype, the mechanism(s) by which PHEX mutations inhibit FGF-23 degradation and/or enhance production remains unknown. Here we show that treatment of wild-type mice with the proprotein convertase (PC) inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone (Dec), increases serum FGF-23 and produces the HYP phenotype. Because PC2 is uniquely colocalized with PHEX in osteoblasts/bone, we examined if PC2 regulates PHEX-dependent FGF-23 cleavage and production. Transfection of murine osteoblasts with PC2 and its chaperone protein 7B2 cleaved FGF-23, whereas Signe1 (7B2) RNA interference (RNAi) transfection, which limited 7B2 protein production, decreased FGF-23 degradation and increased Fgf-23 mRNA and protein. The mechanism by which decreased 7B2*PC2 activity influences Fgf-23 mRNA was linked to reduced conversion of the precursor to bone morphogenetic protein 1 (proBMP1) to active BMP1, which resulted in limited cleavage of dentin matrix acidic phosphoprotein 1 (DMP1), and consequent increased Fgf-23 mRNA. The significance of decreased 7B2*PC2 activity in XLH was confirmed by studies of hyp-mouse bone, which revealed significantly decreased Sgne1 (7B2) mRNA and 7B2 protein, and limited cleavage of proPC2 to active PC2. The expected downstream effects of these changes included decreased FGF-23 cleavage and increased FGF-23 synthesis, secondary to decreased BMP1-mediated degradation of DMP1. Subsequent Hexa-D-arginine treatment of hyp-mice enhanced bone 7B2*PC2 activity, normalized FGF-23 degradation and production, and rescued the HYP phenotype. These data suggest that decreased PHEX-dependent 7B2*PC2 activity is central to the pathogenesis of XLH.

The furin inhibitor hexa-D-arginine blocks the activation of Pseudomonas aeruginosa exotoxin A in vivo.[Pubmed:12438396]

Infect Immun. 2002 Dec;70(12):7136-9.

The Pseudomonas aeruginosa exotoxin A (PEA) protein requires furin-mediated cleavage for manifestation of toxicity. We show here that the small stable furin inhibitor Hexa-D-arginine amide effectively blocks PEA-induced cell lysis and is itself noncytotoxic. Administration of Hexa-D-arginine to PEA-treated mice significantly improves their survival rate and also decreases circulating levels of tumor necrosis factor alpha.

Polyarginines are potent furin inhibitors.[Pubmed:10958789]

J Biol Chem. 2000 Nov 24;275(47):36741-9.

The ubiquitous serine endoprotease furin has been implicated in the activation of bacterial toxins and viral glycoproteins as well as in the metastatic progression of certain tumors. Although high molecular mass bioengineered serpin inhibitors have been well characterized, no small nontoxic nanomolar inhibitors have been reported to date. Here we describe the identification of such inhibitors using positional scanning amidated and acetylated synthetic l- and d-hexapeptide combinatorial libraries. The results indicated that l-Arg or l-Lys in all positions generated the most potent inhibitors. However, further investigation revealed that the peptide terminating groups hindered inhibition. Consequently, a series of non-amidated and acetylated polyarginines was synthesized. The most potent inhibitor identified, nona-l-arginine, had a K(i) for furin of 40 nm. The K(i) values for the related convertases PACE4 and prohormone convertase-1 (PC1) were 110 nm and 2.5 microm, respectively. Although nona-l-arginine was cleaved by furin, the major products after a 6-h incubation at 37 degrees C were hexa- and hepta-l-arginines, both of which retained the great majority of their potency and specificity against furin. Hexa-D-arginine was as potent and specific a furin inhibitor as hexa-l-arginine (K(i) values of Hexa-D-arginine: 106 nm, 580 nm, and 13.2 microm for furin, PACE4, and PC1, respectively). PC2 was not inhibited by any polyarginine tested; indeed, PC2 showed an increase in activity of up to 140% of the control in the presence of l-polyarginines. Data are also presented that show extended subsite recognition by furin and PC2. Whereas N-terminal acetylation was found to reduce the inhibitory potency of the l-hexapeptide LLRVKR against furin 8-fold, C-terminal amidation reduced the potency < 2-fold. Conversely, N-terminal acetylation increased the potency against PC2 nearly 3-fold, whereas C-terminal amidation of the same peptide increased the potency by a factor of 1.6. Our data indicate that non-acetylated, poly-d-arginine-derived molecules may represent excellent lead compounds for the development of therapeutically useful furin inhibitors.

Hexa-D-arginine (Furin Inhibitor II) is a stable furin inhibitor with Ki values 106 nM, 580 nM and 13.2 μM for furin, PACE4 and prohormone convertase-1 (PC1), respectively. Hexa-D-arginine blocks Pseudomonas exotoxin A and anthrax toxins toxicity in vitro and in vivo.

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