FOXO4-DRI

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FOXO4-DRI
FOXO4-DRI structure.png
Identifiers
  • (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
CAS Number
PubChem CID
Chemical and physical data
Formula C228H388N86O64
Molar mass 5358.150 g·mol−1
3D model (JSmol)
  • CC[C@@H](C)[C@H](C(=O)N[C@H](C)C(=O)N[C@H](CCC(=O)N)C(=O)N[C@H](CO)C(=O)N[C@H]([C@H](C)CC)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCC(=O)O)C(=O)N[C@H](C)C(=O)N[C@H](CC1=CC=C(C=C1)O)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(=O)N)C(=O)N[C@H](CC(=O)N)C(=O)NCC(=O)N[C@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@H](C)C(=O)N[C@H](CC(=O)N)C(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](CO)C(=O)NCC(=O)NCC(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCNC(=N)N)C(=O)N4CCC[C@@H]4C(=O)N5CCC[C@@H]5C(=O)N6CCC[C@@H]6C(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](CCC(=O)N)C(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](CCCNC(=N)N)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCNC(=N)N)C(=O)NCC(=O)O)NC(=O)[C@@H](CCC(=O)O)NC(=O)[C@@H](CO)NC(=O)[C@@H](C)NC(=O)[C@H]7CCCN7C(=O)[C@@H](CCC(=O)O)NC(=O)[C@@H](CCCCN)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H]([C@H](C)O)NC(=O)[C@@H](CC(C)C)N
  • 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
  • Key:WVZCDZFJLXBWHG-XXZPGMBKSA-N

FOXO4-DRI is a synthetic peptide derivative that is described as an all D-enantiomer retro-inverso peptide [1] having the sequence H-ltlrkepaseiaqsileaysqngwanrrsggkrppprrrqrrkkrg-OH. [2] It blocks the activity of Forkhead box protein O4 (FOXO4), a transcription factor which is elevated in senescent cells, and helps maintain their viability. Blocking FOXO4 causes senescent cells to undergo apoptosis without affecting healthy cells around them, and has anti-aging effects which may have potential applications in the treatment of numerous age-related diseases, as well as an adjunct to treatment for certain forms of cancer. [3] [4] [5] [6] [7] [8] [9] [10]

References

  1. ↑ Doti N, Mardirossian M, Sandomenico A, Ruvo M, Caporale A (August 2021). "Recent Applications of Retro-Inverso Peptides". International Journal of Molecular Sciences. 22 (16): 8677. doi: 10.3390/ijms22168677 . PMC   8395423 . PMID   34445382.
  2. ↑ Baar MP, Brandt RM, Putavet DA, Klein JD, Derks KW, Bourgeois BR, et al. (March 2017). "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging". Cell. 169 (1): 132–147.e16. doi:10.1016/j.cell.2017.02.031. PMC   5556182 . PMID   28340339.
  3. ↑ Krimpenfort P, Berns A (March 2017). "Rejuvenation by Therapeutic Elimination of Senescent Cells". Cell. 169 (1): 3–5. doi:10.1016/j.cell.2017.03.014. PMID   28340347.
  4. ↑ van Willigenburg H, de Keizer PL, de Bruin RW (April 2018). "Cellular senescence as a therapeutic target to improve renal transplantation outcome". Pharmacological Research. 130: 322–330. doi: 10.1016/j.phrs.2018.02.015 . PMID   29471104.
  5. ↑ Zhang C, Xie Y, Chen H, Lv L, Yao J, Zhang M, et al. (January 2020). "FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice". Aging. 12 (2): 1272–1284. doi:10.18632/aging.102682. PMC   7053614 . PMID   31959736.
  6. ↑ Meng J, Li Y, Wan C, Sun Y, Dai X, Huang J, et al. (December 2021). "Targeting senescence-like fibroblasts radiosensitizes non-small cell lung cancer and reduces radiation-induced pulmonary fibrosis". JCI Insight. 6 (23) e146334. doi:10.1172/jci.insight.146334. PMC   8675198 . PMID   34877934.
  7. ↑ Liu Y, Hou Q, Wang R, Liu Y, Cheng Z (October 2023). "FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice". Naunyn-schmiedeberg's Archives of Pharmacology. 396 (10): 2393–2403. doi:10.1007/s00210-023-02452-2. PMID   37074394.
  8. ↑ Li Y, Zhang C, Cheng H, Lv L, Zhu X, Ma M, et al. (October 2024). "FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells". Experimental Gerontology. 195 112522. doi: 10.1016/j.exger.2024.112522 . PMID   39025385.
  9. ↑ Kong YX, Li ZS, Liu YB, Pan B, Fu X, Xiao R, et al. (February 2025). "FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation". Communications Biology. 8 (1) 299. doi:10.1038/s42003-025-07738-0. PMC   11850796 . PMID   39994346.
  10. ↑ Bourgeois B, Spreitzer E, Platero-Rochart D, Paar M, Zhou Q, Usluer S, et al. (July 2025). "The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI". Nature Communications. 16 (1) 5672. Bibcode:2025NatCo..16.5672B. doi:10.1038/s41467-025-60844-9. PMC   12216184 . PMID   40593617.
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