Table 1 |.

Interfacial inhibitors identified/developed to date

Drugs	Origin	Substrates	Mechanism of action	Medical use*	Refs
α-amanitin	Black cap mushroom	RNA polymerase II	Binds to Rpb1–Rpb2 interface and prevents Pol II translocation	Not reported	60,61
Adriamycin (doxorubicin) and anthracyclines	Soil bacteria (Streptomyces peucetius)	TOP2-DNA complex	Trap cleavage complexes by binding at the enzyme–DNA interface	FDA-approved	28
Anabaseine	Sea worm (Paranemertes peregrina)	α7 nicotinic acetylcholine receptor (homopentamer)	Agonizes α7 nicotinic acetylcholine receptor by binding at the interface between each of the α7 subunit monomers	Not reported	62
Anaesthetics (desflurane and propofol)	Synthetic	Pentameric ligand-gated ion channels	Act as ion channel blockers	FDA-approved	63
Benzodiazepines	Synthetic	GABAA receptor	Increase conduction of chloride ion channels	FDA-approved	64
Brefeldin A	Fungus (Eupenicillium brefeldianum)	ARF•GDP–GEF complex	Stabilizes a kinetic protein–protein intermediate undergoing conformational changes	Not reported	65,66
Camptothecin	Chinese tree (Camptotheca acuminata)	TOP1–DNA complex	Stabilizes a kinetic intermediate of the enzymatic DNA cleavage reaction	FDA-approved	5,18
Colchicine	Crocus (Colchicum autumnale)	Tubulin heterodimer	Prevents tubulin polymerization by stabilizing a curved tubulin heterodimer	FDA-approved	67
Curares	Plant (Strychnos toxifera)	Nicotinic acetylcholine receptor	Act as nicotinic acetylcholine receptor blockers	Not reported	53
Cyclosporine	Soil fungus (Tolypocladium inflatum)	Cyclophilin–Calcineurin complex	Hinders access to the active site of the protein phosphatase calcineurin by artificially creating a protein–protein interface	FDA-approved	68,69
Dexrazoxane (ICRF-187)	Synthetic	TOP2–ATP complex	Stabilizes the closed TOP2 dimer	FDA-approved	41,70
Ecteinascidin 743	Sea squirt (Ecteinascidia turbinata)	Transcription-coupled nucleotide excision repair	Poisons the repair complex after incision of the DNA by preventing normal repair ligation	Clinically approved	71
Epothilone A	Soil-dwelling myxobacterium (Sorangium cellulosum)	β-tubulin	Stabilizes microtubules	FDA-approved	72
Etoposide and teniposide	Synthetic	TOP2–DNA complex	Stabilize a kinetic intermediate of the enzymatic DNA cleavage reaction	FDA-approved	16
Tacrolimus (FK506)	Soil bacteria Streptomyces tsukubaensis	FKBP–calcineurin complex	Hinders access to the active site of the protein phosphatase calcineurin by artificially creating a protein–protein interface	FDA-approved	73,74
Forskolin	Indian Coleus plant (Coleus forskohlii)	Heterodimer of cytoplasmic domains of adenylyl cyclase	Activates the enzyme by stabilizing the heterodimer catalytic site in an active conformation	Not reported	75
Fusicoccin	Plant parasite fungus (Fusicoccum amygdali)	14-3-3–ATPase complex	Overstabilizes a regulatory complex	Not reported	76
Fusidic acid	Fungus (Fusidium coccineum)	Bacterial ribosome	Stabilizes the translation elongation factor EF-G	Clinically approved	77,78
Indenoisoquinolines	Synthetic	TOP1-DNA complex	Stabilizes a kinetic intermediate of the enzymatic DNA cleavage reaction	In Phase I trials	7,79
Kirromycin	Fungus (Streptomyces collinus)	Antibiotics, bacterial ribosomes	Stabilizes translation elongation factor Tu	Not reported	77,78
Mitoxantrone	Synthetic	TOP2–DNA complex	Stabilizes a kinetic intermediate of the enzymatic DNA cleavage reaction	FDA-approved	16‡
Nalidixic acid and quinolone antibiotics	Synthetic	Gyrase–DNA or topoisomerase IV–DNA complexes	Trap cleavage complexes by binding at the interface between DNA gyrase or topoisomerase IV subunits and DNA	FDA-approved	10–12
Nicotine	Plant (Nicotiana tabacum)	Nicotinic acetylcholine receptor	Increases activity of nicotinic acetylcholine receptors	FDA-approved	53
Raltegravir, elvitegravir and dolutegravir	Synthetic	HIV-1 integrase–DNA complexes	Chelate metal ions in the catalytic site of the integrase–DNA complex	FDA-approved and in Phase III trials	13,15,45
Rapamycin (sirolimus)	Soil bacteria (Streptomyces hygroscopicus)	FKBP–mTOR complex	Promotes dimerization of FKBP12 with mTOR and inhibits mTOR	FDA-approved	80
SAHM1	Stapled peptide	Notch transcription factor complex	Antagonizes Notch signalling pathway and cell proliferation by binding to the intracellular domain of Notch 1 and the DNA-bound CSL transcription factor	Not reported	81
Simocyclinone	Bacteria (Streptomyces antibioticus)	DNA gyrase subunit A homotetramer	Poisons DNA gyrase by binding at the DNA gyrase A59 subunit homotetramer interface	Not reported	82
Paclitaxel and docetaxel	Trees (Taxus baccata, Taxus brevifolia)	β-tubulin	Stabilize microtubules	FDA-approved	83
Thiostrepton	Bacteria (Streptomyces azureus, Streptomyces laurentii)	Bacterial ribosome	Prevents EF-G binding by altering the interface between ribosomal protein L11 and ribosomal RNA	Veterinary use	84
Vinblastine	Madagascar periwinkle plant (Catharanthus roseus)	Tubulin heterodimer	Prevents tubulin polymerization by stabilizing a curved tubulin heterodimer	FDA-approved	44

ARF, ADP-ribosylation factor; CSL, DNA-binding protein complex consisting of the mammalian protein CBF1 (also known as RBPJ-κ), the Drosophila melanogaster protein Su(H) and the Caenorhabditis elegans protein LAG1; FDA, US Food and Drug Administration; FKBP, FK506-binding protein; GABA_A, γ-aminobutyric acid type A; GEF, guanine nucleotide exchange factor; mTOR, mammalian target of rapamycin; Pol II, DNA polymerase II; Rpb1, RNA polymerase II subunit 1; Rpb2, RNA polymerase II subunit 2; SAHM1, stapled α-helical peptides derived from mastermind like-1 (MAML1); TOP1, topoisomerase I; TOP2, topoisomerase II.

^*A large fraction (20 out of 30 drug classes listed) of these interfacial inhibitors are in clinical use (approved by the FDA, approved outside the United States, or in clinical trials.

^‡The mechanism of action of mitoxantrone as a TOP2–DNA interfacial inhibitor was reported at the 2011 Topoisomerase conference in Taipei, Taiwan, October 2011, by the group of Nei-Li Chan, National Taiwan University¹⁶.