TY - JOUR
T1 - New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses
AU - Siniavin, Andrei E.
AU - Gushchin, Vladimir A.
AU - Shastina, Natal'ya S.
AU - Darnotuk, Elizaveta S.
AU - Luyksaar, Sergey I.
AU - Russu, Leonid I.
AU - Inshakova, Anna M.
AU - Shidlovskaya, Elena V.
AU - Vasina, Daria V.
AU - Kuznetsova, Nadezhda A.
AU - Savina, Daria M.
AU - Zorkov, Ilya D.
AU - Dolzhikova, Inna V.
AU - Sheremet, Anna B.
AU - Logunov, Denis Y.
AU - Zigangirova, Nailya A.
AU - Gintsburg, Alexander L.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/5
Y1 - 2024/5
N2 - The spread of COVID-19 continues due to genetic variation in SARS-CoV-2. Highly mutated variants of SARS-CoV-2 have an increased transmissibility and immune evasion. Due to the emergence of various new variants of the virus, there is an urgent need to develop broadly effective specific drugs for therapeutic strategies for the prevention and treatment of COVID-19. Molnupiravir (EIDD-2801, MK-4482), is an orally bioavailable ribonucleoside analogue of β-D-N4-hydroxycytidine (NHC), has demonstrated efficacy against SARS-CoV-2 and was recently approved for COVID-19 treatment. To improve antiviral potency of NHC, we developed a panel of NHC conjugates with lipophilic vectors and ester derivatives with amino- and carboxylic-acids. Most of the synthesized compounds had comparable or higher (2–20 times) antiviral activity than EIDD-2801, against different lineages of SARS-CoV-2, MERS-CoV, seasonal coronaviruses OC43 and 229E, as well as bovine coronavirus. For further studies, we assessed the most promising compound in terms of activity, simplicity and cost of synthesis - NHC conjugate with phenylpropionic acid (SN_9). SN_9 has shown high efficacy in prophylactic, therapeutic and transmission models of COVID-19 infection in hamsters. Importantly, SN_9 profoundly inhibited virus replication in the lower respiratory tract of hamsters and transgenic mice infected with the Omicron sublineages XBB.1.9.1, XBB.1.16 and EG.5.1.1. These data indicate that SN_9 represents a promising antiviral drug candidate for COVID-19 treatment, and NHC modification strategies deserve further investigation as an approach to develop prodrugs against various coronaviruses.
AB - The spread of COVID-19 continues due to genetic variation in SARS-CoV-2. Highly mutated variants of SARS-CoV-2 have an increased transmissibility and immune evasion. Due to the emergence of various new variants of the virus, there is an urgent need to develop broadly effective specific drugs for therapeutic strategies for the prevention and treatment of COVID-19. Molnupiravir (EIDD-2801, MK-4482), is an orally bioavailable ribonucleoside analogue of β-D-N4-hydroxycytidine (NHC), has demonstrated efficacy against SARS-CoV-2 and was recently approved for COVID-19 treatment. To improve antiviral potency of NHC, we developed a panel of NHC conjugates with lipophilic vectors and ester derivatives with amino- and carboxylic-acids. Most of the synthesized compounds had comparable or higher (2–20 times) antiviral activity than EIDD-2801, against different lineages of SARS-CoV-2, MERS-CoV, seasonal coronaviruses OC43 and 229E, as well as bovine coronavirus. For further studies, we assessed the most promising compound in terms of activity, simplicity and cost of synthesis - NHC conjugate with phenylpropionic acid (SN_9). SN_9 has shown high efficacy in prophylactic, therapeutic and transmission models of COVID-19 infection in hamsters. Importantly, SN_9 profoundly inhibited virus replication in the lower respiratory tract of hamsters and transgenic mice infected with the Omicron sublineages XBB.1.9.1, XBB.1.16 and EG.5.1.1. These data indicate that SN_9 represents a promising antiviral drug candidate for COVID-19 treatment, and NHC modification strategies deserve further investigation as an approach to develop prodrugs against various coronaviruses.
KW - Antiviral
KW - Coronaviruses
KW - Esters
KW - N4-hydroxycytidine
KW - Prodrug
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85189917133&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85189917133&partnerID=8YFLogxK
U2 - 10.1016/j.antiviral.2024.105871
DO - 10.1016/j.antiviral.2024.105871
M3 - Article
C2 - 38555022
AN - SCOPUS:85189917133
SN - 0166-3542
VL - 225
JO - Antiviral research
JF - Antiviral research
M1 - 105871
ER -