Literature summary for 3.1.13.2 extracted from

Yu, F.; Liu, X.; Zhan, P.; De Clercq, E.
Recent advances in the research of HIV-1 RNase H inhibitors (2008), Mini Rev. Med. Chem., 8, 1243-1251.

Application

Application	Comment	Organism
drug development	development of anti-HIV agents which can be used alone or in the combination with other HIV inhibitors in AIDS chemotherapy	Human immunodeficiency virus 1

Crystallization (Commentary)

Crystallization (Comment)	Organism
-	Human immunodeficiency virus 1

Protein Variants

Protein Variants	Comment	Organism
K103N/Y181C	non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant mutant	Human immunodeficiency virus 1
V106A/Y181C	non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant mutant	Human immunodeficiency virus 1

Inhibitors

Inhibitors	Comment	Organism
(2E)-2-[(4-chlorophenyl)hydrazono]propanoic acid	4-chlorophenylhydrazone of pyruvic acid, shows poor inhibitory activity against HIV-1 RNase H because of the storage of one or two carboxylic acid moieties	Human immunodeficiency virus 1
(2Z)-2-hydroxy-4-oxopent-2-enoic acid	-	Human immunodeficiency virus 1
1,3,4,5-tetragalloylapiitol	extracted from the plant Hylodendron gabunense, also inhibitory effective against HIV-2 RNase H	Human immunodeficiency virus 1
1,4-Naphthoquinone	-	Human immunodeficiency virus 1
1-(4-chlorophenyl)-2-(1-methylethylidene)hydrazine	4-chlorophenylhydrazone of acetone, shows poor inhibitory activity against HIV-1 RNase H because of the storage of one or two carboxylic acid moieties	Human immunodeficiency virus 1
2,7-dihydroxy-4-isopropylcyclohepta-2,4,6-trienone	beta-thujaplicinol, tropolone derivative. Inhibitory activity against both HIV-1 RNase H and Escherichia coli RNase H at a concentration of 0.2 microM and 50 microM respectively	Human immunodeficiency virus 1
2-amino-12-ethyl-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one	mappicine analogue	Human immunodeficiency virus 1
2-aminoisoquinoline-1,3(2H,4H)-dione	-	Human immunodeficiency virus 1
2-chloro-7-(2-cyclohexyl-1-hydroxyethyl)-8-methyl-12-propylindolizino[1,2-b]quinolin-9(11H)-one	mappicine analogue	Human immunodeficiency virus 1
2-hydroxyisoquinoline-1,3(2H,4H)-dione	best inhibitor with high selectivity and activity	Human immunodeficiency virus 1
2-methoxyisoquinoline-1,3(2H,4H)-dione	-	Human immunodeficiency virus 1
3'-azido-3'-deoxythymidine 5'-(dihydrogen phosphate)	inhibits RNase H in vitro, but is not selectively active against RNase H. Does not exhibit inhibitory activity against RNase H in the HIV-1 replication process	Human immunodeficiency virus 1
3-[(E)-[4-[(E)-2-carboxyethenyl]phenyl]diazenyl]-7-[([6-[(E)-[4-[(E)-2-carboxyethenyl]phenyl]diazenyl]-5-hydroxy-7-sulfonatonaphthalen-2-yl]carbamoyl)amino]-4-hydroxynaphthalene-2-sulfonate	-	Human immunodeficiency virus 1
4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutanoic acid	L-731,988	Human immunodeficiency virus 1
4-[5-(benzoylamino)tien-2-yl]-2,4-dioxobutanoic acid	diketo acid derivative	Human immunodeficiency virus 1
5-chloro-2-hydroxyisoquinoline-1,3(2H,4H)-dione	-	Human immunodeficiency virus 1
acetylshikonin	inhibits weakly	Human immunodeficiency virus 1
alpha-thujaplicin	tropolone derivative	Human immunodeficiency virus 1
ardimerin digallate	from natural plant of Ardisia japonica	Human immunodeficiency virus 1
beta-thujaplicin	tropolone derivative	Human immunodeficiency virus 1
deoxyshikonin	inhibits weakly	Human immunodeficiency virus 1
Dextran sulfate	inhibits RNase H in vitro, but is not selectively active against RNase H. Does not exhibit inhibitory activity against RNase H in the HIV-1 replication process	Human immunodeficiency virus 1
dihydroxy benzoyl naphthyl hydrazone	also have inhibitory activity against drug-resistant HIV-1 RT variants Y181C RT and Y188l RT. NNRTI Efavirenz shows no inhibitory effect under the same conditions	Human immunodeficiency virus 1
ethyl (5E)-6-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxohex-5-enoate	RDS 1643, good selectivity and high potency in enzyme and cell culture assay	Human immunodeficiency virus 1
gamma-thujaplicin	tropolone derivative	Human immunodeficiency virus 1
heparin	inhibits RNase H in vitro, but is not selectively active against RNase H. Does not exhibit inhibitory activity against RNase H in the HIV-1 replication process	Human immunodeficiency virus 1
illimaquinone	inhibits RNase H in vitro, but is not selectively active against RNase H. Does not exhibit inhibitory activity against RNase H in the HIV-1 replication process	Human immunodeficiency virus 1
juglone	poor inhibitory activity	Human immunodeficiency virus 1
manicol	tropolone derivative. Inhibitory activity against both HIV-1 RNase H and Escherichia coli RNase H at a concentration of 1.5 microM and 40 microM respectively	Human immunodeficiency virus 1
additional information	summary of HIV-1 RNase H inhibitors. Ardimerin has no inhibitory activity against HIV-1 RNase H because of the absence of galloyl unit. Oligonucleotide with 35 base pairs based on the G-quartet inhibits the RNase H and the polymerase. Different oligonucleotides with structural characters of hairpins and dumbbells: 1R4RR4, 2R4RR4, 3R4RR4, 4D4RD4, 5R4D4R, 6R6RR6, 7R6RR6, 8nicked dumbbell, and 9ligared dumbbell. Effective, they do not inhibit the polymerase and RNase H of Mammalia	Human immunodeficiency virus 1
N-(4-tert-butylbenzoyl)-2-hydroxy-1-naphthaldehyde hydrazone	phenylhydrazone derivative. Inhibits RNase H in vitro, but is not selectively active against RNase H. Exhibits inhibitory activity against RNase H in the HIV-1 replication process	Human immunodeficiency virus 1
naphthazarin	inhibits weakly	Human immunodeficiency virus 1
Plumbagin	poor inhibitory activity	Human immunodeficiency virus 1
shikometabolin C	inhibits weakly	Human immunodeficiency virus 1
shikometabolin D	inhibits weakly	Human immunodeficiency virus 1
shikonin	inhibits weakly	Human immunodeficiency virus 1
tert-butyl [7-(1-hydroxypropyl)-8-methyl-9-oxo-12-(trimethylsilyl)-9,11-dihydroindolizino[1,2-b]quinolin-2-yl]carbamate	mappicine analogue	Human immunodeficiency virus 1
tropolone	-	Human immunodeficiency virus 1
vitamin K6	-	Human immunodeficiency virus 1
[(4-chlorophenyl)hydrazono]propanedioic acid	inhibits by directly chelating Mg2+	Human immunodeficiency virus 1

Metals/Ions

Metals/Ions	Comment	Organism
Mg2+	only binds to the RNase H active site	Human immunodeficiency virus 1
Mn2+	binds to the active sites of both polymerase and RNase H	Human immunodeficiency virus 1
additional information	metal ions are cofactors for the catalytic activities of HIV-1 RNase H domains	Human immunodeficiency virus 1

Organism

Organism	UniProt	Comment	Textmining
Human immunodeficiency virus 1	-	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
CGK1 + H2O	RNase H substrate CGK1 is obtained by annealing 5'-cap-labelled R1 5'-m7Gppp*GmAAUACUCAAGCUAUGCAUC-3' with DNA oligonucleotide D1. The RNA oligonucleotide is blocked at the 5' end by adding a guanosyl-5'-5'-guanosine triphosphate cap structure	Human immunodeficiency virus 1	?	-	?
DNA-RNA duplex + H2O	-	Human immunodeficiency virus 1	?	-	?
single-stranded RNA + H2O	-	Human immunodeficiency virus 1	?	-	?

Synonyms

Synonyms	Comment	Organism
RNase H	-	Human immunodeficiency virus 1

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
additional information	-	IC50 values of different oligonucleotides with structural characters of hairpins and dumbbells: 0.000500 mM for oligonucleotide with 35 base pairs based on the G-quartet motif, 0.0258 mM for 1R4RR4, 0.0262 mM for 2R4RR4, 0.0693 mM for 3R4RR4, 0.0078 mM for 6R6RR6, 0.0297 mM for 7R6RR6, 0.0404 mM for 8nicked dumbbell, and 0.0033 mM for 9ligared dumbbell. IC50 value is much higher than 100 microM for 4D4RD4 and 5R4D4R. [(4-chlorophenyl)hydrazono] propanedioic acid shows an IC50 value of 3 microM against polymerase-independent RNase H activity. Its activity against HIV-1 RNase H in vivo and toxicity in cell culture or in vivo still need to be investigated. IC50 0.0013 mM for 3,7-dihydroxy-tropolone, monosubstituted, and 0.0047 mM for 3,7-dihydroxy-tropolone, unsubstituted	Human immunodeficiency virus 1	additional information
0.00024	-	also inhibitory effective against HIV-2 RNase H with an IC50 value of 0.13 microM. Poor selectivity against human RNase H with an IC50 value of 1.5 microM	Human immunodeficiency virus 1	1,3,4,5-tetragalloylapiitol
0.00038	-	inhibits the isolated HIV RNase H domain	Human immunodeficiency virus 1	5-chloro-2-hydroxyisoquinoline-1,3(2H,4H)-dione
0.00043	-	inhibits the isolated HIV RNase H domain in the assay using CGK1 as substrate	Human immunodeficiency virus 1	2-hydroxyisoquinoline-1,3(2H,4H)-dione
0.0005	-	-	Human immunodeficiency virus 1	dihydroxy benzoyl naphthyl hydrazone
0.0006	-	using CGK1 as substrate	Human immunodeficiency virus 1	2-hydroxyisoquinoline-1,3(2H,4H)-dione
0.00065	-	drug-resistant HIV-1 reverse transcriptase variant Y181C reverse transcriptase	Human immunodeficiency virus 1	dihydroxy benzoyl naphthyl hydrazone
0.001	-	in another assay, using poly(dC:rG) as a template, without inhibitory effect against Escherichia coli RNase H	Human immunodeficiency virus 1	2-hydroxyisoquinoline-1,3(2H,4H)-dione
0.0012	-	drug-resistant HIV-1 reverse transcriptase variant Y188l reverse transcriptase	Human immunodeficiency virus 1	dihydroxy benzoyl naphthyl hydrazone
0.0015	-	without inhibiting both human and Escherichia coli RNase H at a concentration of 200 microM/l	Human immunodeficiency virus 1	ardimerin digallate
0.0032	-	HIV-1 RNase H inhibitor, which inhibits the HIV-1 RNase H as part of HIV-reverse transcriptase without influencing the activity of HIV-1-dependent RNA and DNA polymerase	Human immunodeficiency virus 1	4-[5-(benzoylamino)tien-2-yl]-2,4-dioxobutanoic acid
0.0047	-	isolated HIV-RNAse H domain	Human immunodeficiency virus 1	4-[5-(benzoylamino)tien-2-yl]-2,4-dioxobutanoic acid
0.0095	-	-	Human immunodeficiency virus 1	1,4-Naphthoquinone
0.013	-	-	Human immunodeficiency virus 1	ethyl (5E)-6-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxohex-5-enoate