Modification of N-hydroxycytidine yields a novel lead compound exhibiting activity against the Venezuelan equine encephalitis virus
Published by Elsevier Ltd..
Nucleoside and nucleobase analogs capable of interfering with nucleic acid synthesis have played essential roles in fighting infectious diseases. However, many of these agents are associated with important and potentially lethal off-target intracellular effects that limit their use. Based on the previous discovery of base-modified 2'-deoxyuridines, which showed high anticancer activity while exhibiting lower toxicity toward rapidly dividing normal human cells compared to antimetabolite chemotherapeutics, we hypothesized that a similar modification of the N4-hydroxycytidine (NHC) molecule would provide novel antiviral compounds with diminished side effects. This presumption is due to the substantial structural difference with natural cytidine leading to less recognizability by host cell enzymes. Among the 42 antimetabolite species that have been synthesized and screened against VEEV, one hit compound was identified. The structural features of the modifying moiety were similar to those of the anticancer lead 2'-deoxyuridine derivative reported previously, providing an opportunity to pursue further structure-activity relationship (SAR) studies directed to lead improvement, and obtain insight into the mechanism of action, which can lead to identifying drug candidates against a broad spectrum of RNA viral infections.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:94 |
|---|---|
| Enthalten in: |
Bioorganic & medicinal chemistry letters - 94(2023) vom: 01. Okt., Seite 129432 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Downs, Isaac L [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 25.09.2023 Date Revised 25.09.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bmcl.2023.129432 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM360902014 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM360902014 | ||
| 003 | DE-627 | ||
| 005 | 20231226084014.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bmcl.2023.129432 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1202.xml |
| 035 | |a (DE-627)NLM360902014 | ||
| 035 | |a (NLM)37591319 | ||
| 035 | |a (PII)S0960-894X(23)00310-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Downs, Isaac L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Modification of N-hydroxycytidine yields a novel lead compound exhibiting activity against the Venezuelan equine encephalitis virus |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.09.2023 | ||
| 500 | |a Date Revised 25.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Published by Elsevier Ltd. | ||
| 520 | |a Nucleoside and nucleobase analogs capable of interfering with nucleic acid synthesis have played essential roles in fighting infectious diseases. However, many of these agents are associated with important and potentially lethal off-target intracellular effects that limit their use. Based on the previous discovery of base-modified 2'-deoxyuridines, which showed high anticancer activity while exhibiting lower toxicity toward rapidly dividing normal human cells compared to antimetabolite chemotherapeutics, we hypothesized that a similar modification of the N4-hydroxycytidine (NHC) molecule would provide novel antiviral compounds with diminished side effects. This presumption is due to the substantial structural difference with natural cytidine leading to less recognizability by host cell enzymes. Among the 42 antimetabolite species that have been synthesized and screened against VEEV, one hit compound was identified. The structural features of the modifying moiety were similar to those of the anticancer lead 2'-deoxyuridine derivative reported previously, providing an opportunity to pursue further structure-activity relationship (SAR) studies directed to lead improvement, and obtain insight into the mechanism of action, which can lead to identifying drug candidates against a broad spectrum of RNA viral infections | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Antimetabolites | |
| 650 | 4 | |a Modified nucleobases | |
| 650 | 4 | |a N-hydroxycytidine | |
| 650 | 4 | |a Nucleosides | |
| 650 | 4 | |a VEEV | |
| 650 | 7 | |a Antimetabolites |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Deoxyuridine |2 NLM | |
| 650 | 7 | |a W78I7AY22C |2 NLM | |
| 650 | 7 | |a Immunosuppressive Agents |2 NLM | |
| 650 | 7 | |a N(4)-hydroxycytidine |2 NLM | |
| 650 | 7 | |a C3D11PV2O4 |2 NLM | |
| 700 | 1 | |a David Ordonez Luna, A |e verfasserin |4 aut | |
| 700 | 1 | |a Kota, Krishna P |e verfasserin |4 aut | |
| 700 | 1 | |a Rubin, Sarah K |e verfasserin |4 aut | |
| 700 | 1 | |a Shirsekar, Serena S |e verfasserin |4 aut | |
| 700 | 1 | |a Ward, Michael D |e verfasserin |4 aut | |
| 700 | 1 | |a Panchal, Rekha G |e verfasserin |4 aut | |
| 700 | 1 | |a Litosh, Vladislav A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Bioorganic & medicinal chemistry letters |d 1992 |g 94(2023) vom: 01. Okt., Seite 129432 |w (DE-627)NLM09063828X |x 1464-3405 |7 nnns |
| 773 | 1 | 8 | |g volume:94 |g year:2023 |g day:01 |g month:10 |g pages:129432 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bmcl.2023.129432 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 94 |j 2023 |b 01 |c 10 |h 129432 | ||