Nepidermin - Misplaced Pages

(Redirected from RhEGF) Chemical compound

Pharmaceutical compound

Nepidermin
Clinical data
Trade names	Heberprot-P, Easyef, Genesoft, Kang He Su, Regen-D
Other names	Recombinant human epidermal growth factor; rhEGF; DWP-401
Routes of administration	intralesional injection; Topical
Identifiers
IUPAC name H-Asn-Ser-Asp-Ser-Glu-Cys-Pro-Leu-Ser-His-Asp-Gly-Tyr-Cys-Leu-His-Asp-Gly-Val-Cys-Met-Tyr-Ile-Glu-Ala-Leu-Asp-Lys-Tyr-Ala-Cys-Asn-Cys-Val-Val-Gly-Tyr-Ile-Gly-Glu-Arg-Cys-Gln-Tyr-Arg-Asp-Leu-Lys-Trp-Trp-Glu-Leu-Arg-OH
CAS Number	62253-63-8
PubChem CID	16143379
ChemSpider	17299876
UNII	TZK30RF92W
CompTox Dashboard (EPA)	DTXSID80211314
ECHA InfoCard	100.241.060
Chemical and physical data
Formula	C₂₇₀H₄₀₁N₇₃O₈₃S₇
Molar mass	6222.03 g·mol
3D model (JSmol)	Interactive image
SMILES CC(C)(C(=O)NCC(=O)N(CCC(=O)O)C(=O)N(CCCNC(=N)N)C(=O)N(CS)C(=O)N(CCC(=O)N)C(=O)N(CC1=CC=C(C=C1)O)C(=O)N(CCCNC(=N)N)C(=O)N(CC(=O)O)C(=O)N(CC(C)C)C(=O)N(CCCCN)C(=O)N(CC2=CNC3=CC=CC=C32)C(=O)N(CC4=CNC5=CC=CC=C54)C(=O)N(CCC(=O)O)C(=O)N(CC(C)C)C(=O)N(CCCNC(=N)N)C(=O)O)NC(=O)(CC6=CC=C(C=C6)O)NC(=O)CNC(=O)(C(C)C)NC(=O)(C(C)C)NC(=O)(CS)NC(=O)(CC(=O)N)NC(=O)(CS)NC(=O)(C)NC(=O)(CC7=CC=C(C=C7)O)NC(=O)(CCCCN)NC(=O)(CC(=O)O)NC(=O)(CC(C)C)NC(=O)(C)NC(=O)(CCC(=O)O)NC(=O)((C)CC)NC(=O)(CC8=CC=C(C=C8)O)NC(=O)(CCSC)NC(=O)(CS)NC(=O)(C(C)C)NC(=O)CNC(=O)(CC(=O)O)NC(=O)(CC9=CN=CN9)NC(=O)(CC(C)C)NC(=O)(CS)NC(=O)(CC1=CC=C(C=C1)O)NC(=O)CNC(=O)(CC(=O)O)NC(=O)(CC1=CN=CN1)NC(=O)(CO)NC(=O)(CC(C)C)NC(=O)1CCCN1C(=O)(CS)NC(=O)(CCC(=O)O)NC(=O)(CO)NC(=O)(CC(=O)O)NC(=O)(CO)NC(=O)(CC(=O)N)N
InChI InChI=1S/C270H401N73O83S7/c1-24-134(19)217(262(420)293-112-201(355)298-161(69-74-205(359)360)229(387)301-160(45-35-82-286-269(279)280)228(386)333-192(119-428)255(413)307-162(68-73-198(274)352)230(388)316-176(94-141-54-64-150(350)65-55-141)241(399)304-159(44-34-81-285-268(277)278)227(385)325-186(105-212(373)374)248(406)313-169(87-127(5)6)235(393)302-158(43-31-33-80-272)226(384)318-179(97-144-108-289-156-41-29-27-39-153(144)156)243(401)319-178(96-143-107-288-155-40-28-26-38-152(143)155)242(400)305-164(71-76-207(363)364)231(389)312-170(88-128(7)8)236(394)310-167(267(425)426)46-36-83-287-270(281)282)341-250(408)174(92-139-50-60-148(348)61-51-139)300-203(357)113-292-261(419)214(131(13)14)340-264(422)216(133(17)18)339-259(417)195(122-431)335-246(404)182(101-200(276)354)322-257(415)191(118-427)332-220(378)137(22)297-234(392)175(93-140-52-62-149(349)63-53-140)315-225(383)157(42-30-32-79-271)303-247(405)185(104-211(371)372)326-237(395)168(86-126(3)4)311-219(377)136(21)296-224(382)163(70-75-206(361)362)309-265(423)218(135(20)25-2)342-251(409)177(95-142-56-66-151(351)67-57-142)317-233(391)166(78-85-433-23)308-256(414)194(121-430)336-263(421)215(132(15)16)338-204(358)114-291-223(381)184(103-210(369)370)323-244(402)180(98-145-109-283-124-294-145)320-238(396)171(89-129(9)10)314-258(416)193(120-429)334-240(398)173(91-138-48-58-147(347)59-49-138)299-202(356)111-290-222(380)183(102-209(367)368)324-245(403)181(99-146-110-284-125-295-146)321-254(412)190(117-346)330-239(397)172(90-130(11)12)328-260(418)197-47-37-84-343(197)266(424)196(123-432)337-232(390)165(72-77-208(365)366)306-252(410)189(116-345)331-249(407)187(106-213(375)376)327-253(411)188(115-344)329-221(379)154(273)100-199(275)353/h26-29,38-41,48-67,107-110,124-137,154,157-197,214-218,288-289,344-351,427-432H,24-25,30-37,42-47,68-106,111-123,271-273H2,1-23H3,(H2,274,352)(H2,275,353)(H2,276,354)(H,283,294)(H,284,295)(H,290,380)(H,291,381)(H,292,419)(H,293,420)(H,296,382)(H,297,392)(H,298,355)(H,299,356)(H,300,357)(H,301,387)(H,302,393)(H,303,405)(H,304,399)(H,305,400)(H,306,410)(H,307,413)(H,308,414)(H,309,423)(H,310,394)(H,311,377)(H,312,389)(H,313,406)(H,314,416)(H,315,383)(H,316,388)(H,317,391)(H,318,384)(H,319,401)(H,320,396)(H,321,412)(H,322,415)(H,323,402)(H,324,403)(H,325,385)(H,326,395)(H,327,411)(H,328,418)(H,329,379)(H,330,397)(H,331,407)(H,332,378)(H,333,386)(H,334,398)(H,335,404)(H,336,421)(H,337,390)(H,338,358)(H,339,417)(H,340,422)(H,341,408)(H,342,409)(H,359,360)(H,361,362)(H,363,364)(H,365,366)(H,367,368)(H,369,370)(H,371,372)(H,373,374)(H,375,376)(H,425,426)(H4,277,278,285)(H4,279,280,286)(H4,281,282,287)/t134-,135-,136-,137-,154-,157-,158-,159-,160-,161-,162-,163-,164-,165-,166-,167-,168-,169-,170-,171-,172-,173-,174-,175-,176-,177-,178-,179-,180-,181-,182-,183-,184-,185-,186-,187-,188-,189-,190-,191-,192-,193-,194-,195-,196-,197-,214-,215-,216-,217-,218-/m0/s1 Key:GVUGOAYIVIDWIO-UFWWTJHBSA-N

Nepidermin (INN proposed), also known as recombinant human epidermal growth factor (rhEGF), is a recombinant form of human epidermal growth factor (EGF) and a cicatrizant (a drug that promotes wound healing through formation of scar tissue). As a recombinant form of EGF, nepidermin is an agonist of the epidermal growth factor receptor (EGFR), and is the first EGFR agonist to be marketed. It was developed by Cuban Center for Genetic Engineering and Biotechnology (CIBG), and has been marketed by Heber Biotech as an intralesional injection for diabetic foot ulcer under the trade name Heberprot-P since 2006. As of 2016, Heberprot-P had been marketed in 23 countries, but remains unavailable in the United States. In 2015, preparations were made to conduct the Phase III trials required for FDA approval, however as of 2023 developments in U.S.-Cuba relations have stymied importation of the drug from Cuba.

Various forms of rhEGF are marketed for the treatment of diabetic foot ulcers, wounds, and alopecia (hair loss) in Vietnam, the Philippines, Thailand, and China.

Production

According to Heber Biotech, nepidermin is made by insering the 53-amino acid human EGF sequence into yeast. A 1991 paper from Cuba seems to describe its production in more detail. An improved process was described in 2009.

Other rhEGFs

Several other products containing recombinant human EGF have been marketed. The potencies of these products can differ by the expression system used, despite all intending to match the structure of human EGF.

Instead of measuring by mass, the international unit system from the World Health Organization provides a way to describe the potency-adjusted amount of rhEGF. However, the WHO does not prescribe a specific way of measuring the potency. rhEGF bioassay remains a field in active development.

Easyef

This section is missing information about approval status, specifically for this one. Please expand the section to include this information. Further details may exist on the talk page. (December 2023)

A topical spray formulation has been developed under the brand Easyef by Daewoong Pharmaceutical.

A Daewoong-funded Phase II study evaluating nepidermin oral spray for chemotherapy-induced oral mucositis did not reduce incidence or duration of moderate or severe oral mucositis, however per-protocol analysis suggested nepidermin oral spray might reduce pain associated with oral mucositis.

Easyef is made by expression in E. coli. It appears to be less potent than an equivalent concentration of Heberprot in zebrafish.

Other preparations

List of rhEGF preparations
Brand name	Manufacturer	Form	Indication	Description
Heberprot-P	Heber (Cuba)	Lyophilized powder	Ulcer	See above. Drugs.com reports marketing in Vietnam and Georgia.
Easyef	Daewoong (Korea)	Spray	Ulcer, wounds	See above. Drugs.com reports marketing in Thailand and Vietnam.
Genesoft (金因舒)	Uni-Bio (Hong Kong); Licensed to GeneTech (China)	Eye drop	Corneal damage (?)	Approved in China (Rx, 国药准字 S20040006). Yeast expression system.
GeneTime (金因肽)	Uni-Bio (Hong Kong); Licensed to GeneTech (China)	Spray		Approved in China (Rx, 国药准字 S20010037–8). E. coli expression system.
Kang He Su (康合素)	Haohai (China)	Lyophilized powder	second-degree burns, wounds, ulcers	Approved in China (Rx, 国药准字 S20010094–6, S20010099). To be used as a part of wound dressing, soaked in gauze. E. coli expression system.
Yi Fu (易孚)		Gel	second-degree burns, wounds, ulcers	Approved in China (Rx). Yeast expression system.
Regen-D	Bharat Biotech (India)	Gel	Diabetic foot ulcer	Approved in India and Thailand. E. coli expression system. Bharat also markets a gel with silver sulfadiazine and chlorhexidine for burns.

References

^ "Nepidermin". Drugs.com. Archived from the original on 2017-12-13. Retrieved 3 June 2017.
"INN Proposed List 97". www.who.int.
^ "Nepidermin". AdisInsight. Springer Nature Switzerland AG. Retrieved 3 June 2017.
^ Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, et al. (2016). "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation. 10 (1): 403–423. doi:10.1007/s40005-016-0268-6. PMC 7052475. PMID 32166015. S2CID 17779371.
Berlanga J, Fernández JI, López E, López PA, del Río A, Valenzuela C, et al. (January 2013). "Heberprot-P: a novel product for treating advanced diabetic foot ulcer". MEDICC Review. 15 (1): 11–15. doi:10.37757/MR2013V15.N1.4. PMID 23396236.
Fernández-Montequín JI, Betancourt BY, Leyva-Gonzalez G, Mola EL, Galán-Naranjo K, Ramírez-Navas M, et al. (February 2009). "Intralesional administration of epidermal growth factor-based formulation (Heberprot-P) in chronic diabetic foot ulcer: treatment up to complete wound closure". International Wound Journal. 6 (1): 67–72. doi:10.1111/j.1742-481X.2008.00561.x. PMC 7951202. PMID 19291119.
"Heberprot-P registered in 23 countries". National Network on Cuba. 10 June 2016. Retrieved 2023-01-16.
Brenner A (2018-03-22). "U.S. and Cuban companies reach agreement on Heberprot-p". The Cuban Handshake. Retrieved 2023-01-16.
Clinical trial number NCT02554851 for "Efficacy and Safety Evaluation of the Intralesional Recombinant Human Epidermal Growth Factor (rhEGF) in Subjects With Diabetic Foot Ulcer. Multicenter, Randomized, Double-blind, Placebo-controlled Study." at ClinicalTrials.gov The Immunobiological Technology Institute (Bio-Manguinhos) / Oswaldo Cruz Foundation (Fiocruz)
"Heberprot-P brochure for professionals" (PDF). Retrieved 29 December 2023.
Cinza AM, Quintana M, Lambardero R, Pontón R, Pérez E, Pérez LC, et al. (1991). "Establecimiento de un cultivo discontinuo para la producción del factor de crecimiento epidérmico humano en levaduras: caracterización del producto" [A batch process for production of human epidermal growth factor in yeast.]. Biotecnologia Aplicada (in Spanish). 8 (2): 166–73.
Valdés J, Mantilla E, Márquez G, Bonilla RM, Lugo VM, Pérez M, et al. (2009). "Improving the expression of human epidermal growth factor in Saccharomyces cerevisiae by manipulating culture conditions" (PDF). Biotecnologia Aplicada. 26 (1): 34–38. ISSN 0864-4551.
^ Cho KH, Kim JH, Nam HS, Kang DJ (April 2022). "Efficacy Comparison Study of Human Epidermal Growth Factor (EGF) between Heberprot-P and Easyef in Adult Zebrafish and Embryo under Presence or Absence Combination of Diabetic Condition and Hyperlipidemia to Mimic Elderly Patients". Geriatrics. 7 (2). doi:10.3390/geriatrics7020045. PMC 9028627. PMID 35447848.
"Epidermal Growth Factor (Human, rDNA derived) WHO International Standard". nibsc.org.
"Unit Conversion Table". R&D Systems. – Provides information on "unit" conversion of a number of hormones. According to the table, this supplier's rhEGF is 1.4 times as potent as the reference 91/530 at the same mass.
Qin X, Yao W, Shi X, Liu L, Huang F, Ding Y, et al. (March 2019). "Responsive Cells for rhEGF bioassay Obtained through Screening of a CRISPR/Cas9 Library". Scientific Reports. 9 (1): 3780. Bibcode:2019NatSR...9.3780Q. doi:10.1038/s41598-019-40381-4. PMC 6405917. PMID 30846752.
Kim JW, Kim MG, Lee HJ, Koh Y, Kwon JH, Kim I, et al. (2017-01-03). "Topical Recombinant Human Epidermal Growth Factor for Oral Mucositis Induced by Intensive Chemotherapy with Hematopoietic Stem Cell Transplantation: Final Analysis of a Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial". PLOS ONE. 12 (1): e0168854. Bibcode:2017PLoSO..1268854K. doi:10.1371/journal.pone.0168854. PMC 5207736. PMID 28045958.
"GENESOFT(EGF Eyedrop)". www.uni-bioscience.com.
"人表皮生长因子滴眼液 ". 中国药典 [Pharmacopoeia of the People's Republic of China]. Vol. 3.
"人表皮生长因子外用溶液（I）". 中国药典 [Pharmacopoeia of the People's Republic of China]. Vol. 3.
"外用重组人表皮生长因子说明书" [Package insert: rhEGF for external use] (PDF). 3healthcare.com. Retrieved 29 December 2023.
"外用人表皮生长因子 ". 中国药典 [Pharmacopoeia of the People's Republic of China]. Vol. 3.
"易孚人表皮生长因子凝胶(酵母)说明书(5万IU(100μg)*10g）-" [Package insert: Yi Fu hEGF gel (Yeast), 50000IU(100μg)*10g]. 亮健好药网手机端 (in Chinese).
"人表皮生长因子凝胶 ". 中国药典 [Pharmacopoeia of the People's Republic of China]. Vol. 3.
"Regen-D 150|Faster Healing of Foot Ulcers Gel-". Bharat Biotech. – Manufacturer page with PDFs
Mohan VK (December 2007). "Recombinant human epidermal growth factor (REGEN-D 150): effect on healing of diabetic foot ulcers". Diabetes Research and Clinical Practice. 78 (3): 405–411. doi:10.1016/j.diabres.2007.06.004. PMID 17655964.
"SLVRGEN| Wound Healing Epidermal Growth Gel". Bharat Biotech.

v t e Preparations for treatment of wounds and ulcers (D03)
Cicatrizants	epichlorohydrin: Cadexomer iodine Crilanomer Dextranomer B5: Calcium pantothenate Dexpanthenol nitrate: Nitroglycerin Isosorbide dinitrate other: Becaplermin Beremagene geperpavec Betulae cortex Centella asiatica herba Enoxolone Hyaluronic acid Ketanserin Nepidermin Sodium chlorite (tetrachlorodecaoxide) Trafermin Trolamine
Proteolytic enzymes	Bromelain (anacaulase) Clostridiopeptidase Trypsin

Preparations for treatment of wounds and ulcers (D03)

Cicatrizants

B5: Calcium pantothenate
Dexpanthenol

Proteolytic enzymes

v t e Other dermatological preparations (D11)
Anti-seborrheics	Antiandrogens Bicalutamide Cyproterone acetate Flutamide Spironolactone Antifungals Bifonazole Cetrimonium bromide (cetrimide) Ciclopirox olamine (ciclopirox) Climbazole Clotrimazole Ketoconazole Miconazole Piroctone olamine Selenium disulfide (selenium sulfide) Xenysalate Zinc pyrithione (pyrithione zinc) Antihistamines Calcineurin inhibitors Cyclosporin Pimecrolimus Tacrolimus Isotretinoin Keratolytics Coal tar Resorcinol Salicylic acid Sulfur Urea (urea-containing cream) Lithium salts Lithium gluconate Lithium succinate Topical corticosteroids (e.g., hydrocortisone)
Skin lightening	Hydroquinone Mequinol Monobenzone
Skin darkening	Afamelanotide Melanotan II
Anti-inflammatories	Alitretinoin Gamolenic acid Oxaceprol Pimecrolimus Tacrolimus Topical corticosteroids (e.g., hydrocortisone)
Alopecia treatments	5α-Reductase inhibitors Alfatradiol Dutasteride Finasteride Saw palmetto extract Antiandrogens Bicalutamide Cyproterone acetate Flutamide Spironolactone Topilutamide (fluridil) Potassium channel openers Minoxidil Others Nepidermin Ritlecitinib
Hair growth inhibitors	5α-Reductase inhibitors Dutasteride Finasteride Antiandrogens Bicalutamide Cyproterone acetate Flutamide Spironolactone Eflornithine
Others	Abrocitinib Aminobenzoate potassium Androgens (e.g., testosterone) Benzoylperoxide Brimonidine Caffeine Calcium gluconate Collagen Crisaborole Cromoglicic acid Delgocitinib Deoxycholic acid Diclofenac Dupilumab Estrogens (e.g., estradiol) Glycopyrronium bromide Glycopyrronium tosylate Hyaluronic acid Hydrogen peroxide Ivermectin Lebrikizumab Lokivetmab Magnesium sulfate Metandienone Nemolizumab Oclacitinib Oxymetazoline Povidone-iodine Pregnenolone acetate Progestogens (e.g., progesterone) Ruxolitinib Tiratricol Tralokinumab

Growth factor receptor modulators

Angiopoietin

Agonists: Angiopoietin 1
Angiopoietin 4

Antagonists: Angiopoietin 2
Angiopoietin 3

Kinase inhibitors: Altiratinib
CE-245677
Rebastinib

Antibodies: Evinacumab (against angiopoietin 3)
Nesvacumab (against angiopoietin 2)

CNTF

Agonists: Axokine
CNTF
Dapiclermin

EGF (ErbB)

EGF (ErbB1/HER1)	Agonists: Amphiregulin Betacellulin EGF (urogastrone) Epigen Epiregulin Heparin-binding EGF-like growth factor (HB-EGF) Murodermin Nepidermin Transforming growth factor alpha (TGFα) Kinase inhibitors: Afatinib Agerafenib Brigatinib Canertinib Dacomitinib Erlotinib Gefitinib Grandinin Icotinib Lapatinib Neratinib Osimertinib Vandetanib WHI-P 154 Antibodies: Cetuximab Depatuxizumab Depatuxizumab mafodotin Futuximab Imgatuzumab Matuzumab Necitumumab Nimotuzumab Panitumumab Zalutumumab
ErbB2/HER2	Agonists: Unknown/none Antibodies: Ertumaxomab Pertuzumab Trastuzumab Trastuzumab deruxtecan Trastuzumab duocarmazine Trastuzumab emtansine Kinase inhibitors: Afatinib Lapatinib Mubritinib Neratinib Tucatinib
ErbB3/HER3	Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C)) Antibodies: Duligotumab Patritumab Seribantumab
ErbB4/HER4	Agonists: Betacellulin Epigen Heparin-binding EGF-like growth factor (HB-EGF) Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))

FGF

FGFR1	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20) Repifermin Selpercatinib Trafermin Velafermin
FGFR2	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22) Palifermin Repifermin Selpercatinib Sprifermin Trafermin Antibodies: Aprutumab Aprutumab ixadotin Kinase inhibitors: Infigratinib
FGFR3	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 8, 9, 18, 23) Selpercatinib Sprifermin Trafermin Antibodies: Burosumab (against FGF23)
FGFR4	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 6, 8, 9, 19) Trafermin
Unsorted	Agonists: FGF15/19

HGF (c-Met)

Agonists: Fosgonimeton
Hepatocyte growth factor

Potentiators: Dihexa (PNB-0408)

IGF

IGF-1

IGF-2

Agonists: Insulin-like growth factor-2 (somatomedin A)

Antibodies: Dusigitumab
Xentuzumab (against IGF-1 and IGF-2)

Others

Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7)

Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1)
Trofinetide

LNGF (p75)

Antibodies: Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab

Aptamers: Against NGF: RBM-004

Decoy receptors: LEVI-04 (p75-Fc)

PDGF

Agonists: Becaplermin
Platelet-derived growth factor (A, B, C, D)

RET (GFL)

GFRα1	Agonists: Glial cell line-derived neurotrophic factor (GDNF) Liatermin Kinase inhibitors: Vandetanib
GFRα2	Agonists: Neurturin (NRTN) Kinase inhibitors: Vandetanib
GFRα3	Agonists: Artemin (ARTN) Kinase inhibitors: Vandetanib
GFRα4	Agonists: Persephin (PSPN) Kinase inhibitors: Vandetanib
Unsorted	Kinase inhibitors: Agerafenib