Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIQSC1)

• DTT Name: Bacterial Lethal factor (Bact lef)
• Synonyms: lef; Anthrax lethal toxin endopeptidase component; Anthrax lethal factor; ALF
• Gene Name: Bact lef
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: LEF_BACAN
• TTD ID: T72335
• EC Number: EC 3.4.24.83
• Sequence:
  MNIKKEFIKVISMSCLVTAITLSGPVFIPLVQGAGGHGDVGMHVKEKEKNKDENKRKDEE
  RNKTQEEHLKEIMKHIVKIEVKGEEAVKKEAAEKLLEKVPSDVLEMYKAIGGKIYIVDGD
  ITKHISLEALSEDKKKIKDIYGKDALLHEHYVYAKEGYEPVLVIQSSEDYVENTEKALNV
  YYEIGKILSRDILSKINQPYQKFLDVLNTIKNASDSDGQDLLFTNQLKEHPTDFSVEFLE
  QNSNEVQEVFAKAFAYYIEPQHRDVLQLYAPEAFNYMDKFNEQEINLSLEELKDQRMLAR
  YEKWEKIKQHYQHWSDSLSEEGRGLLKKLQIPIEPKKDDIIHSLSQEEKELLKRIQIDSS
  DFLSTEEKEFLKKLQIDIRDSLSEEEKELLNRIQVDSSNPLSEKEKEFLKKLKLDIQPYD
  INQRLQDTGGLIDSPSINLDVRKQYKRDIQNIDALLHQSIGSTLYNKIYLYENMNINNLT
  ATLGADLVDSTDNTKINRGIFNEFKKNFKYSISSNYMIVDINERPALDNERLKWRIQLSP
  DTRAGYLENGKLILQRNIGLEIKDVQIIKQSEKEYIRIDAKVVPKSKIDTKIQEAQLNIN
  QEWNKALGLPKYTKLITFNVHNRYASNIVESAYLILNEWKNNIQSDLIKKVTNYLVDGNG
  RFVFTDITLPNIAEQYTHQDEIYEQVHSKGLYVPESRSILLHGPSKGVELRNDSEGFIHE
  FGHAVDDYAGYLLDKNQSDLVTNSKKFIDIFKEEGSNLTSYGRTNEAEFFAEAFRLMHST
  DHAERLKVQKNAPKTFQFINDQIKFIINS
• Function: One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. LF is the lethal factor that, when associated with PA, causes death. LF is not toxic by itself. It is a protease that cleaves the N-terminal of most dual specificity mitogen-activated protein kinase kinases (MAPKKs or MAP2Ks) (except for MAP2K5). Cleavage invariably occurs within the N-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes. There may be other cytosolic targets of LF involved in cytotoxicity. The proteasome may mediate a toxic process initiated by LF in the cell cytosol involving degradation of unidentified molecules that are essential for macrophage homeostasis. This is an early step in LeTx intoxication, but it is downstream of the cleavage by LF of MEK1 or other putative substrates.
• KEGG Pathway: NOD-like receptor signaling pathway (bar04621)
• Reactome Pathway: Uptake and function of anthrax toxins (R-HSA-5210891)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IQ-DAA	DMHP71R	Bacillus anthracis infection	1G40	Phase 1	[1]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GM6001	DM7V9CT	Corneal ulcer	9A76	Discontinued in Phase 2	[2]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-(2,5-dimethyl-1H-pyrrol-1-yl)benzoic acid	DMUDW1J	Discovery agent	N.A.	Investigative	[3]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[4]
GNF-PF-600	DMWGXBF	Discovery agent	N.A.	Investigative	[5]
MMI270	DM38N2K	Discovery agent	N.A.	Investigative	[6]
N,N'-Bis(4-Amino-2-Methylquinolin-6-Yl)Urea	DMT4USP	Discovery agent	N.A.	Investigative	[2]
N-(3,4,5-trihydroxyphenethyl)oleamide	DMQ5USA	Discovery agent	N.A.	Investigative	[7]
N-(3,4-dihydroxybenzyl)oleamide	DM67XSW	Discovery agent	N.A.	Investigative	[8]
N-(Sulfanylacetyl)Tyrosylprolylmethioninamide	DMWJDYZ	Discovery agent	N.A.	Investigative	[2]
N-hydroxy-4-(2-oleamidoethyl)benzamide	DMKELRB	Discovery agent	N.A.	Investigative	[7]
N-hydroxy-4-(oleamidomethyl)benzamide	DMUSHZK	Discovery agent	N.A.	Investigative	[8]
N-oleoyl-dopamine	DM1AVCZ	Discovery agent	N.A.	Investigative	[7]
NSC-622445	DME35CB	Discovery agent	N.A.	Investigative	[3]

References

• [1] Anti-toxin antibodies in prophylaxis and treatment of inhalation anthrax.Future Microbiol.2009 Feb;4(1):35-43.
• [2] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [3] Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening. J Med Chem. 2006 Aug 24;49(17):5232-44.
• [4] Amiodarone and bepridil inhibit anthrax toxin entry into host cells. Antimicrob Agents Chemother. 2007 Jul;51(7):2403-11.
• [5] Anthrax lethal factor protease inhibitors: synthesis, SAR, and structure-based 3D QSAR studies. J Med Chem. 2006 Jan 12;49(1):27-30.
• [6] The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection. Bioorg Med Chem Lett. 2006 Feb 15;16(4):964-8.
• [7] Inhibitors of anthrax lethal factor. Bioorg Med Chem Lett. 2007 Aug 15;17(16):4575-8.
• [8] Inhibitors of anthrax lethal factor based upon N-oleoyldopamine. Bioorg Med Chem Lett. 2008 Apr 1;18(7):2467-70.