Discovery of Modified Amidate (ProTide) Prodrugs of Tenofovir with Enhanced Antiviral Properties
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F21%3A00547506" target="_blank" >RIV/61388963:_____/21:00547506 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11310/21:10441842
Result on the web
<a href="https://doi.org/10.1021/acs.jmedchem.1c01444" target="_blank" >https://doi.org/10.1021/acs.jmedchem.1c01444</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.jmedchem.1c01444" target="_blank" >10.1021/acs.jmedchem.1c01444</a>
Alternative languages
Result language
angličtina
Original language name
Discovery of Modified Amidate (ProTide) Prodrugs of Tenofovir with Enhanced Antiviral Properties
Original language description
This study describes the discovery of novel prodrugs bearing tyrosine derivatives instead of the phenol moiety present in FDA-approved tenofovir alafenamide fumarate (TAF). The synthesis was optimized to afford diastereomeric mixtures of novel prodrugs in one pot (yields up to 86%), and the epimers were resolved using a chiral HPLC column into fast-eluting and slow-eluting epimers. In human lymphocytes, the most efficient tyrosine-based prodrug reached a single-digit picomolar EC50 value against HIV-1 and nearly 300-fold higher selectivity index (SI) compared to TAF. In human hepatocytes, the most efficient prodrugs exhibited subnanomolar EC50 values for HBV and up to 26-fold higher SI compared to TAF. Metabolic studies demonstrated markedly higher cellular uptake of the prodrugs and substantially higher levels of released tenofovir inside the cells compared to TAF. These promising results provide a strong foundation for further evaluation of the reported prodrugs and their potential utility in the development of highly potent antivirals.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
<a href="/en/project/LTAUSA18086" target="_blank" >LTAUSA18086: Design, synthesis and biological evaluation of potential modulators of human adenylate cyclases</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Medicinal Chemistry
ISSN
0022-2623
e-ISSN
1520-4804
Volume of the periodical
64
Issue of the periodical within the volume
22
Country of publishing house
US - UNITED STATES
Number of pages
25
Pages from-to
16425-16449
UT code for WoS article
000754726000006
EID of the result in the Scopus database
2-s2.0-85118865177