Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTTSOUD)

• DTT Name: Candida Cytochrome P450 51 (Candi ERG11)
• Synonyms: Sterol 14alpha-demethylase; Sterol 14-alpha demethylase; P450LI; P450L1; P450-14DM; Lanosterol 14 alpha-demethylase; LDM; Erg11p; ERG11; Cytochrome P450-dependent lanosterol 14-demethylase; Cytochrome P-450 lanosterol 14-alpha-demethylase; Cyt P450 14DM; CYPLI; CYPL1
• Gene Name: Candi ERG11
• DTT Type: Successful target; [1]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: CP51_CANAL
• TTD ID: T73726
• Sequence:
  MAIVETVIDGINYFLSLSVTQQISILLGVPFVYNLVWQYLYSLRKDRAPLVFYWIPWFGS
  AASYGQQPYEFFESCRQKYGDVFSFMLLGKIMTVYLGPKGHEFVFNAKLSDVSAEDAYKH
  LTTPVFGKGVIYDCPNSRLMEQKKFAKFALTTDSFKRYVPKIREEILNYFVTDESFKLKE
  KTHGVANVMKTQPEITIFTASRSLFGDEMRRIFDRSFAQLYSDLDKGFTPINFVFPNLPL
  PHYWRRDAAQKKISATYMKEIKSRRERGDIDPNRDLIDSLLIHSTYKDGVKMTDQEIANL
  LIGILMGGQHTSASTSAWFLLHLGEKPHLQDVIYQEVVELLKEKGGDLNDLTYEDLQKLP
  SVNNTIKETLRMHMPLHSIFRKVTNPLRIPETNYIVPKGHYVLVSPGYAHTSERYFDNPE
  DFDPTRWDTAAAKANSVSFNSSDEVDYGFGKVSKGVSSPYLPFGGGRHRCIGEQFAYVQL
  GTILTTFVYNLRWTIDGYKVPDPDYSSMVVLPTEPAEIIWEKRETCMF
• Function: Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
• KEGG Pathway:
  Steroid biosynthesis (cal00100)
  Metabolic pathways (cal01100)
  Biosynthesis of secondary metabolites (cal01110)

Molecular Interaction Atlas (MIA) of This DTT

16 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bifonazole	DM3KN7V	Fungal infection	1F29-1F2F	Approved	[1]
Butoconazole	DM8SY60	Candidiasis	1F23	Approved	[2]
Econazole	DMFSWGH	Cutaneous candidiasis	1F23.14	Approved	[3]
Efinaconazole	DMFA9MV	Fungal infection	1F29-1F2F	Approved	[4]
Fluconazole	DMOWZ6B	Cryptococcal meningitis		Approved	[5]
Itraconazole	DMCR1MV	Aspergillosis	1F20	Approved	[5]
Ketoconazole	DMPZI3Q	Blastomycosis	1F22	Approved	[6]
Luliconazole	DMT73J8	Tinea corporis	1F28.Y	Approved	[7]
Miconazole	DMPMYE8	Cutaneous candidiasis	1F23.14	Approved	[5]
Oteseconazole	DM7R145	Vulvovaginal Candidiasis	1F23.10	Approved	[8]
Oxiconazole	DME7KRM	Tinea corporis	1F28.Y	Approved	[9]
Posaconazole	DMUL5EW	Aspergillosis	1F20	Approved	[10]
Sertaconazole	DM1A9XO	Fungal infection	1F29-1F2F	Approved	[11]
Terconazole	DMJ13KI	Candidiasis	1F23	Approved	[12]
Tioconazole	DMNYPGS	Onychomycosis	EE12.1	Approved	[13]
Voriconazole	DMAOL2S	Aspergillosis	1F20	Approved	[5]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CHLORIDE	DM1TJXA	Solid tumour/cancer	2A00-2F9Z	Phase 3	[14]
E-1224	DMLS269	Fungal infection	1F29-1F2F	Phase 2	[15]
EcoNail	DM1LDIP	Fungal infection	1F29-1F2F	Phase 2	[16]
Pramiconazole	DMBH7XI	Dermatological disease	DA24.Y	Phase 2	[17]
Embeconazole	DM6AMKZ	Fungal infection	1F29-1F2F	Phase 1	[18]
Genaconazole	DMWR93D	Fungal infection	1F29-1F2F	Phase 1	[19]
VT-1598	DM8HBW0	Coccidioidomycosis	1F25	Phase 1	[20]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Abafungin	DM09GSW	Fungal infection	1F29-1F2F	Discontinued in Phase 3	[21]
AZALANSTAT	DMV1ES3	Hyperlipidaemia	5C80	Discontinued in Phase 2	[22]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ANALOGUE A	DM5JN3P	Discovery agent	N.A.	Investigative	[23]
citric acid	DM80YI7	Discovery agent	N.A.	Investigative	[24]
CP-320626	DMY8O0B	Discovery agent	N.A.	Investigative	[23]

References

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• [2] Effects of terconazole and other azole antifungal agents on the sterol and carbohydrate composition of Candida albicans. Diagn Microbiol Infect Dis. 1990 Jan-Feb;13(1):31-5.
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• [12] Mode of action of anti-Candida drugs: focus on terconazole and other ergosterol biosynthesis inhibitors. Am J Obstet Gynecol. 1991 Oct;165(4 Pt 2):1193-9.
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• [14] Isavuconazonium: first global approval. Drugs. 2015 May;75(7):817-22.
• [15] Recent Developments in Sterol 14-demethylase Inhibitors for Chagas Disease. Int J Parasitol Drugs Drug Resist. 2012 Dec;2:236-242.
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• [17] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [18] CS-758. Antifungal lanosterol 14alpha-demethylase inhibitor, 003, vol28, no3, 217-223.
• [19] New targets and delivery systems for antifungal therapy. Med Mycol. 2000;38 Suppl 1:335-47.
• [20] The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis. Med Mycol. 2020 Jun 1;58(4):505-513.
• [21] Upregulation of sterol C14-demethylase expression in Trypanosoma cruzi treated with sterol biosynthesis inhibitors. Mol Biochem Parasitol. 2005 Nov;144(1):68-75.
• [22] Azalanstat (RS-21607), a lanosterol 14 alpha-demethylase inhibitor with cholesterol-lowering activity. Biochem Pharmacol. 1995 Aug 8;50(4):529-44.
• [23] Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors. Drug Metab Dispos. 2007 Mar;35(3):493-500.
• [24] Chemosensitization of fluconazole resistance in Saccharomyces cerevisiae and pathogenic fungi by a D-octapeptide derivative. Antimicrob Agents Chemother. 2004 Apr;48(4):1256-71.