Peptide-β-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes
The β-lactam ring represents a valuable moiety that can induce covalent binding of an inhibitor to its target. In this study, we explored di- and tripeptides with β-lactam electrophilic warheads as inhibitors of dengue and West Nile virus NS2B-NS3 protease. Tripeptides with a (3S)-β-lactam moiety di...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
2020
|
| In: |
Journal of medicinal chemistry
Year: 2019, Volume: 63, Issue: 1, Pages: 140-156 |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.9b00759 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1021/acs.jmedchem.9b00759
|
| Author Notes: | Tonko Dražić, Sara Kopf, James Corridan, Mila M. Leuthold, Branimir Bertoša, and Christian D. Klein |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 169035383X | ||
| 003 | DE-627 | ||
| 005 | 20230427083242.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 200219r20202019xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.9b00759 |2 doi | |
| 035 | |a (DE-627)169035383X | ||
| 035 | |a (DE-599)KXP169035383X | ||
| 035 | |a (OCoLC)1341306976 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Dražić, Tonko |e VerfasserIn |0 (DE-588)1172444226 |0 (DE-627)1041207751 |0 (DE-576)514624736 |4 aut | |
| 245 | 1 | 0 | |a Peptide-β-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes |c Tonko Dražić, Sara Kopf, James Corridan, Mila M. Leuthold, Branimir Bertoša, and Christian D. Klein |
| 246 | 3 | 3 | |a Peptide-beta-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes |
| 264 | 1 | |c 2020 | |
| 300 | |a 17 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Published online 5 December 2019 | ||
| 500 | |a Gesehen am 19.02.2020 | ||
| 520 | |a The β-lactam ring represents a valuable moiety that can induce covalent binding of an inhibitor to its target. In this study, we explored di- and tripeptides with β-lactam electrophilic warheads as inhibitors of dengue and West Nile virus NS2B-NS3 protease. Tripeptides with a (3S)-β-lactam moiety displayed the highest activity, with IC50 and EC50 values in the lower micromolar range in biochemical and cellular assays. The activity against dengue protease was in general higher than against West Nile virus protease. The compounds were inactive against the off-targets thrombin and trypsin. Liquid chromatography-mass spectrometry experiments revealed that tripeptide-β-lactam inhibitors bind to the protease in two distinct binding modes. Only one binding mode leads to a covalent, but reversible, interaction of the β-lactam ring with the catalytic serine, followed by release of the inhibitor with opened β-lactam ring. The other binding mode leads to the cleavage of the peptide backbone. This observation provides the first experimental evidence that benzyloxyphenylglycine in flaviviral protease inhibitors is positioned in the prime site of the enzyme. | ||
| 534 | |c 2019 | ||
| 700 | 1 | |a Leuthold, Mila |e VerfasserIn |0 (DE-588)1113305134 |0 (DE-627)867172029 |0 (DE-576)476948304 |4 aut | |
| 700 | 1 | |a Klein, Christian D. |e VerfasserIn |0 (DE-588)1060644894 |0 (DE-627)800410157 |0 (DE-576)416768717 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d Washington, DC : ACS, 1959 |g 63(2020), 1, Seite 140-156 |h Online-Ressource |w (DE-627)302468846 |w (DE-600)1491411-6 |w (DE-576)090855132 |x 1520-4804 |7 nnas |a Peptide-β-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes |
| 773 | 1 | 8 | |g volume:63 |g year:2020 |g number:1 |g pages:140-156 |g extent:17 |a Peptide-β-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes |
| 856 | 4 | 0 | |u https://doi.org/10.1021/acs.jmedchem.9b00759 |x Verlag |x Resolving-System |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20200219 | ||
| 993 | |a Article | ||
| 994 | |a 2020 | ||
| 998 | |g 1060644894 |a Klein, Christian D. |m 1060644894:Klein, Christian D. |d 160000 |d 160100 |e 160000PK1060644894 |e 160100PK1060644894 |k 0/160000/ |k 1/160000/160100/ |p 6 |y j | ||
| 998 | |g 1113305134 |a Leuthold, Mila |m 1113305134:Leuthold, Mila |d 160000 |d 160100 |e 160000PL1113305134 |e 160100PL1113305134 |k 0/160000/ |k 1/160000/160100/ |p 4 | ||
| 998 | |g 1172444226 |a Dražić, Tonko |m 1172444226:Dražić, Tonko |d 160000 |d 160100 |e 160000PD1172444226 |e 160100PD1172444226 |k 0/160000/ |k 1/160000/160100/ |p 1 |x j | ||
| 999 | |a KXP-PPN169035383X |e 3596772621 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"recId":"169035383X","physDesc":[{"extent":"17 S."}],"title":[{"title_sort":"Peptide-β-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes","title":"Peptide-β-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes"}],"note":["Published online 5 December 2019","Gesehen am 19.02.2020"],"language":["eng"],"type":{"media":"Online-Ressource","bibl":"article-journal"},"relHost":[{"recId":"302468846","physDesc":[{"extent":"Online-Ressource"}],"disp":"Peptide-β-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modesJournal of medicinal chemistry","origin":[{"dateIssuedDisp":"1959-","dateIssuedKey":"1959","publisherPlace":"Washington, DC ; Easton, Pa.","publisher":"ACS ; ACS"}],"title":[{"title_sort":"Journal of medicinal chemistry","title":"Journal of medicinal chemistry"}],"language":["eng"],"type":{"bibl":"periodical","media":"Online-Ressource"},"note":["Gesehen am 02.10.2020"],"name":{"displayForm":["American Chemical Society"]},"pubHistory":["1.1959 -"],"id":{"issn":["1520-4804"],"eki":["302468846"],"zdb":["1491411-6"]},"part":{"year":"2020","volume":"63","pages":"140-156","text":"63(2020), 1, Seite 140-156","extent":"17","issue":"1"}}],"person":[{"family":"Dražić","role":"aut","given":"Tonko","display":"Dražić, Tonko"},{"role":"aut","given":"Mila","family":"Leuthold","display":"Leuthold, Mila"},{"display":"Klein, Christian D.","given":"Christian D.","role":"aut","family":"Klein"}],"origin":[{"dateIssuedDisp":"2020","dateIssuedKey":"2020"}],"id":{"eki":["169035383X"],"doi":["10.1021/acs.jmedchem.9b00759"]},"titleAlt":[{"title":"Peptide-beta-lactam inhibitors of Dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes"}],"name":{"displayForm":["Tonko Dražić, Sara Kopf, James Corridan, Mila M. Leuthold, Branimir Bertoša, and Christian D. Klein"]}} | ||
| SRT | |a DRAZICTONKPEPTIDELAC2020 | ||