PF‐07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID‐19 patients
Abstract The ongoing pandemic of severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) and subsequently, coronavirus disease 2019 (COVID‐19), has led to the deaths of over 6.1 million people and sparked a greater interest in virology to expedite the development process for antivirals. The US...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-07-01
|
| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13292 |
| _version_ | 1818005607843627008 |
|---|---|
| author | Raymond K. Hau Stephen H. Wright Nathan J. Cherrington |
| author_facet | Raymond K. Hau Stephen H. Wright Nathan J. Cherrington |
| author_sort | Raymond K. Hau |
| collection | DOAJ |
| description | Abstract The ongoing pandemic of severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) and subsequently, coronavirus disease 2019 (COVID‐19), has led to the deaths of over 6.1 million people and sparked a greater interest in virology to expedite the development process for antivirals. The US Food and Drug Administration (FDA) granted emergency use authorization for three antivirals: remdesivir, molnupiravir, and nirmatrelvir. Remdesivir and molnupiravir are nucleoside analogs that undergo biotransformation to form active metabolites that incorporate into new viral RNA to stall replication. Unlike remdesivir or molnupiravir, nirmatrelvir is a protease inhibitor that covalently binds to the SARS‐CoV‐2 3C‐like protease to interrupt the viral replication cycle. A recent study identified that remdesivir and the active metabolite of molnupiravir, EIDD‐1931, are substrates of equilibrative nucleoside transporters 1 and 2 (ENT1 and 2). Despite the ubiquitous expression of the ENTs, the preclinical efficacy of remdesivir and molnupiravir is not reflected in wide‐scale SARS‐CoV‐2 clinical trials. Interestingly, downregulation of ENT1 and ENT2 expression has been shown in lung epithelial and endothelial cells in response to hypoxia and acute lung injury, although it has not been directly studied in patients with COVID‐19. It is possible that the poor efficacy of remdesivir and molnupiravir in these patients may be partially attributed to the repression of ENTs in the lungs, but further studies are warranted. This study investigated the interaction between nirmatrelvir and the ENTs and found that it was a poor inhibitor of ENT‐mediated [3H]uridine uptake at 300 μM. Unlike for remdesivir or EIDD‐1931, ENT activity is unlikely to be a factor for nirmatrelvir disposition in humans; however, whether this contributes to the similar in vitro and clinical efficacy will require further mechanistic studies. |
| first_indexed | 2024-04-14T04:46:33Z |
| format | Article |
| id | doaj.art-5d645b29a2fb4323abe83a0b549e26aa |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-14T04:46:33Z |
| publishDate | 2022-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-5d645b29a2fb4323abe83a0b549e26aa2022-12-22T02:11:26ZengWileyClinical and Translational Science1752-80541752-80622022-07-011571599160510.1111/cts.13292PF‐07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID‐19 patientsRaymond K. Hau0Stephen H. Wright1Nathan J. Cherrington2Department of Pharmacology & Toxicology, College of Pharmacy University of Arizona Tucson Arizona USADepartment of Pharmacology & Toxicology, College of Pharmacy University of Arizona Tucson Arizona USADepartment of Physiology, College of Medicine University of Arizona Tucson Arizona USAAbstract The ongoing pandemic of severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) and subsequently, coronavirus disease 2019 (COVID‐19), has led to the deaths of over 6.1 million people and sparked a greater interest in virology to expedite the development process for antivirals. The US Food and Drug Administration (FDA) granted emergency use authorization for three antivirals: remdesivir, molnupiravir, and nirmatrelvir. Remdesivir and molnupiravir are nucleoside analogs that undergo biotransformation to form active metabolites that incorporate into new viral RNA to stall replication. Unlike remdesivir or molnupiravir, nirmatrelvir is a protease inhibitor that covalently binds to the SARS‐CoV‐2 3C‐like protease to interrupt the viral replication cycle. A recent study identified that remdesivir and the active metabolite of molnupiravir, EIDD‐1931, are substrates of equilibrative nucleoside transporters 1 and 2 (ENT1 and 2). Despite the ubiquitous expression of the ENTs, the preclinical efficacy of remdesivir and molnupiravir is not reflected in wide‐scale SARS‐CoV‐2 clinical trials. Interestingly, downregulation of ENT1 and ENT2 expression has been shown in lung epithelial and endothelial cells in response to hypoxia and acute lung injury, although it has not been directly studied in patients with COVID‐19. It is possible that the poor efficacy of remdesivir and molnupiravir in these patients may be partially attributed to the repression of ENTs in the lungs, but further studies are warranted. This study investigated the interaction between nirmatrelvir and the ENTs and found that it was a poor inhibitor of ENT‐mediated [3H]uridine uptake at 300 μM. Unlike for remdesivir or EIDD‐1931, ENT activity is unlikely to be a factor for nirmatrelvir disposition in humans; however, whether this contributes to the similar in vitro and clinical efficacy will require further mechanistic studies.https://doi.org/10.1111/cts.13292 |
| spellingShingle | Raymond K. Hau Stephen H. Wright Nathan J. Cherrington PF‐07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID‐19 patients Clinical and Translational Science |
| title | PF‐07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID‐19 patients |
| title_full | PF‐07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID‐19 patients |
| title_fullStr | PF‐07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID‐19 patients |
| title_full_unstemmed | PF‐07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID‐19 patients |
| title_short | PF‐07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID‐19 patients |
| title_sort | pf 07321332 nirmatrelvir does not interact with human ent1 or ent2 implications for covid 19 patients |
| url | https://doi.org/10.1111/cts.13292 |
| work_keys_str_mv | AT raymondkhau pf07321332nirmatrelvirdoesnotinteractwithhumanent1orent2implicationsforcovid19patients AT stephenhwright pf07321332nirmatrelvirdoesnotinteractwithhumanent1orent2implicationsforcovid19patients AT nathanjcherrington pf07321332nirmatrelvirdoesnotinteractwithhumanent1orent2implicationsforcovid19patients |