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FOXO4-DRI

* Please kindly note that our products are not to be used for therapeutic purposes and cannot be sold to patients.

FOXO4-DRI is a peptide acting as a specific FOXO4 blocker. It has been demonstrated to alleviate age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice.FOXO4-DRI is a peptide acting as a specific FOXO4 blocker. It has been demonstrated to alleviate age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. FOXO4-DRI is a standard FOXO4 protein that is synthesized to prevent normal FOXO4 from binding to p53, thereby eliminating senescent cells and improving organ function and the ''biological age'' of young tissues. FOXO4-DRI affects a variety of cellular processes, including insulin signaling, cell cycle regulation, and oxidative stress signaling pathways, it is a cell-penetrative peptide, meaning it can enter cells from the inside and perform its role, and it has been shown in animal studies to selectively induce apoptosis in senescence cells, potentially reversing some of the effects of aging.

Category

Functional Peptides

Catalog number

BAT-006150

CAS number

2460055-10-9

Molecular Formula

C228H388N86O64

Molecular Weight

5358.05

Size	Price	Stock	Quantity
1 mg	$319	In stock

Specification
Reference Reading

IUPAC Name

(4R)-5-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[(2R)-5-amino-1-[[(2R)-4-amino-1-[[2-[[(2R)-1-[[(2R)-1-[[(2R)-4-amino-1-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[2-[[2-[[(2R)-6-amino-1-[[(2R)-1-[(2R)-2-[(2R)-2-[(2R)-2-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[(2R)-5-amino-1-[[(2R)-1-[[(2R)-1-[[(2R)-6-amino-1-[[(2R)-6-amino-1-[[(2R)-5-carbamimidamido-1-(carboxymethylamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-1,4-dioxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-[[(2R)-2-[[(2R,3R)-2-[[(2R)-2-[[(2R)-5-amino-2-[[(2R)-2-[[(2R,3R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-1-[(2R)-2-[[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R,3S)-2-[[(2R)-2-amino-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-4-carboxybutanoyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-oxopentanoic acid

Synonyms

FOXO 4-DRI; Anti-aging peptide FOXO4-DRI; H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-D-Gly-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-D-Gly-D-Gly-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-OH; Forkhead box O transcription factor 4-D-Retro-Inverso; Proxofim; D-Retro Inverso Forkhead box protein O4; FOXO4-D-retro-inverso; D-leucyl-D-threonyl-D-leucyl-D-arginyl-D-lysyl-D-alpha-glutamyl-D-prolyl-D-alanyl-D-seryl-D-alpha-glutamyl-D-isoleucyl-D-alanyl-D-glutaminyl-D-seryl-D-isoleucyl-D-leucyl-D-alpha-glutamyl-D-alanyl-D-tyrosyl-D-seryl-D-glutaminyl-D-asparagyl-D-glycyl-D-tryptophyl-D-alanyl-D-asparagyl-D-arginyl-D-arginyl-D-seryl-D-glycyl-D-glycyl-D-lysyl-D-arginyl-D-prolyl-D-prolyl-D-prolyl-D-arginyl-D-arginyl-D-arginyl-D-glutaminyl-D-arginyl-D-arginyl-D-lysyl-D-lysyl-D-arginyl-D-glycine

Appearance

White lyophilized powder

Purity

95%

Sequence

D-(LTLRKEPASEIAQSILEAYSQNGWANRRSGGKRPPPRRRQRRKKRG)

Storage

Store at -20 °C

Solubility

Soluble in DMSO, Water

InChI

InChI=1S/C228H388N86O64/c1-16-115(9)174(308-201(361)145(70-76-171(331)332)295-207(367)155(109-316)304-180(340)119(13)276-210(370)158-58-38-92-311(158)216(376)147(71-77-172(333)334)298-196(356)132(47-23-27-81-232)284-192(352)137(53-33-87-264-224(249)250)290-203(363)149(98-114(7)8)303-214(374)176(121(15)319)310-181(341)126(233)96-112(3)4)212(372)277-120(14)177(337)280-141(66-72-162(234)321)200(360)306-157(111-318)209(369)309-175(116(10)17-2)213(373)302-148(97-113(5)6)204(364)293-144(69-75-170(329)330)185(345)274-117(11)178(338)299-150(99-122-62-64-124(320)65-63-122)205(365)307-156(110-317)208(368)294-143(68-74-164(236)323)199(359)301-152(101-165(237)324)183(343)272-106-169(328)279-151(100-123-103-269-127-43-19-18-42-125(123)127)202(362)275-118(12)179(339)300-153(102-166(238)325)206(366)291-138(54-34-88-265-225(251)252)193(353)288-139(55-35-89-266-226(253)254)197(357)305-154(108-315)184(344)271-104-167(326)270-105-168(327)278-129(44-20-24-78-229)186(346)297-146(57-37-91-268-228(257)258)215(375)313-94-40-60-160(313)218(378)314-95-41-61-161(314)217(377)312-93-39-59-159(312)211(371)296-140(56-36-90-267-227(255)256)195(355)287-134(50-30-84-261-221(243)244)190(350)286-136(52-32-86-263-223(247)248)194(354)292-142(67-73-163(235)322)198(358)289-135(51-31-85-262-222(245)246)191(351)285-133(49-29-83-260-220(241)242)189(349)283-131(46-22-26-80-231)188(348)282-130(45-21-25-79-230)187(347)281-128(48-28-82-259-219(239)240)182(342)273-107-173(335)336/h18-19,42-43,62-65,103,112-121,126,128-161,174-176,269,315-320H,16-17,20-41,44-61,66-102,104-111,229-233H2,1-15H3,(H2,234,321)(H2,235,322)(H2,236,323)(H2,237,324)(H2,238,325)(H,270,326)(H,271,344)(H,272,343)(H,273,342)(H,274,345)(H,275,362)(H,276,370)(H,277,372)(H,278,327)(H,279,328)(H,280,337)(H,281,347)(H,282,348)(H,283,349)(H,284,352)(H,285,351)(H,286,350)(H,287,355)(H,288,353)(H,289,358)(H,290,363)(H,291,366)(H,292,354)(H,293,364)(H,294,368)(H,295,367)(H,296,371)(H,297,346)(H,298,356)(H,299,338)(H,300,339)(H,301,359)(H,302,373)(H,303,374)(H,304,340)(H,305,357)(H,306,360)(H,307,365)(H,308,361)(H,309,369)(H,310,341)(H,329,330)(H,331,332)(H,333,334)(H,335,336)(H4,239,240,259)(H4,241,242,260)(H4,243,244,261)(H4,245,246,262)(H4,247,248,263)(H4,249,250,264)(H4,251,252,265)(H4,253,254,266)(H4,255,256,267)(H4,257,258,268)/t115-,116-,117-,118-,119-,120-,121+,126-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,138-,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,174-,175-,176-/m1/s1

InChI Key

WVZCDZFJLXBWHG-XXZPGMBKSA-N

Canonical SMILES

CCC(C)C(C(=O)NC(C)C(=O)NC(CCC(=O)N)C(=O)NC(CO)C(=O)NC(C(C)CC)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(C)C(=O)NC(CC1=CC=C(C=C1)O)C(=O)NC(CO)C(=O)NC(CCC(=O)N)C(=O)NC(CC(=O)N)C(=O)NCC(=O)NC(CC2=CNC3=CC=CC=C32)C(=O)NC(C)C(=O)NC(CC(=O)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CO)C(=O)NCC(=O)NCC(=O)NC(CCCCN)C(=O)NC(CCCNC(=N)N)C(=O)N4CCCC4C(=O)N5CCCC5C(=O)N6CCCC6C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCC(=O)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCNC(=N)N)C(=O)NCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CO)NC(=O)C(C)NC(=O)C7CCCN7C(=O)C(CCC(=O)O)NC(=O)C(CCCCN)NC(=O)C(CCCNC(=N)N)NC(=O)C(CC(C)C)NC(=O)C(C(C)O)NC(=O)C(CC(C)C)N

1. FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice

Chi Zhang, et al. Aging (Albany NY). 2020 Jan 20;12(2):1272-1284. doi: 10.18632/aging.102682. Epub 2020 Jan 20.

Male late-onset hypogonadism is an age-related disease, the core mechanism of which is dysfunction of senescent Leydig cells. Recent studies have shown that elimination of senescent cells can restore proper homeostasis to aging tissue. In the present study, we found that the fork head box O (FOXO) transcription factor FOXO4 was specially expressed in human Leydig cells and that its translocation to the nucleus in the elderly was related to decreased testosterone synthesis. Using hydrogen peroxide-induced senescent TM3 Leydig cells as an in vitro model, we observed that FOXO4 maintains the viability of senescent Leydig cells and suppresses their apoptosis. By disrupting the FOXO4-p53 interaction, FOXO4-DRI, a specific FOXO4 blocker, selectively induced p53 nuclear exclusion and apoptosis in senescent Leydig cells. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.

2. Targeting senescence-like fibroblasts radiosensitizes non-small cell lung cancer and reduces radiation-induced pulmonary fibrosis

Jingshu Meng, et al. JCI Insight. 2021 Dec 8;6(23):e146334. doi: 10.1172/jci.insight.146334.

Cancer cell radioresistance is the primary cause of the decreased curability of non-small cell lung cancer (NSCLC) observed in patients receiving definitive radiotherapy (RT). Following RT, a set of microenvironmental stress responses is triggered, including cell senescence. However, cell senescence is often ignored in designing effective strategies to resolve cancer cell radioresistance. Herein, we identify the senescence-like characteristics of cancer-associated fibroblasts (CAFs) after RT and clarify the formidable ability of senescence-like CAFs in promoting NSCLC cell proliferation and radioresistance through the JAK/STAT pathway. Specific induction of senescence-like CAF apoptosis using FOXO4-DRI, a FOXO4-p53-interfering peptide, resulted in remarkable effects on radiosensitizing NSCLC cells in vitro and in vivo. In addition, in this study, we also uncovered an obvious therapeutic effect of FOXO4-DRI on alleviating radiation-induced pulmonary fibrosis (RIPF) by targeting senescence-like fibroblasts in vivo. In conclusion, by targeting senescence, we offer a strategy that simultaneously decreases radioresistance of NSCLC and the incidence of RIPF.

3. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes

Yuzhao Huang, Yuchen He, Meagan J Makarcyzk, Hang Lin Front Bioeng Biotechnol. 2021 Apr 29;9:677576. doi: 10.3389/fbioe.2021.677576. eCollection 2021.

Autologous chondrocyte implantation (ACI) is a procedure used to treat articular cartilage injuries and prevent the onset of post-traumatic osteoarthritis. In vitro expansion of chondrocytes, a necessary step in ACI, results in the generation of senescent cells that adversely affect the quality and quantity of newly formed cartilage. Recently, a senolytic peptide, fork head box O transcription factor 4-D-Retro-Inverso (FOXO4-DRI), was reported to selectively kill the senescent fibroblasts. In this study, we hypothesized that FOXO4-DRI treatment could remove the senescent cells in the expanded chondrocytes, thus enhancing their potential in generating high-quality cartilage. To simulate the in vitro expansion for ACI, chondrocytes isolated from healthy donors were expanded to population doubling level (PDL) 9, representing chondrocytes ready for implantation. Cells at PDL3 were also used to serve as the minimally expanded control. Results showed that the treatment of FOXO4-DRI removed more than half of the cells in PDL9 but did not significantly affect the cell number of PDL3 chondrocytes. Compared to the untreated control, the senescence level in FOXO4-DRI treated PDL9 chondrocytes was significantly reduced. Based on the result from standard pellet culture, FOXO4-DRI pre-treatment did not enhance the chondrogenic potential of PDL9 chondrocytes. However, the cartilage tissue generated from FOXO4-DRI pretreated PDL9 cells displayed lower expression of senescence-relevant secretory factors than that from the untreated control group. Taken together, FOXO4-DRI is able to remove the senescent cells in PDL9 chondrocytes, but its utility in promoting cartilage formation from the in vitro expanded chondrocytes needs further investigation.