Dual-targeted anti-CMV/anti-HIV-1 heterodimers

Despite the development of efficient anti–human immunodeficiency virus-1 (HIV-1) therapy, HIV-1 associated pathogens remain a major clinical problem. Human cytomegalovirus (CMV) is among the most common HIV-1 copathogens and one of the main causes of persistent immune activation associated with dysr...

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Bibliographic Details
Published in:Biochimie 2021-10, Vol.189, p.169-180
Main Authors: Khandazhinskaya, Anastasia L., Mercurio, Vincenzo, Maslova, Anna A., Ñahui Palomino, Rogers Alberto, Novikov, Mikhail S., Matyugina, Elena S., Paramonova, Maria P., Kukhanova, Marina K., Fedorova, Natalya E., Yurlov, Kirill I., Kushch, Alla A., Tarasova, Olga, Margolis, Leonid, Kochetkov, Sergey N., Vanpouille, Christophe
Format: Article
Language:English
Subjects:
CMV
Heterodimers
HIV-1
Human tissues
Viral diseases
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Summary:Despite the development of efficient anti–human immunodeficiency virus-1 (HIV-1) therapy, HIV-1 associated pathogens remain a major clinical problem. Human cytomegalovirus (CMV) is among the most common HIV-1 copathogens and one of the main causes of persistent immune activation associated with dysregulation of the immune system, cerebrovascular and cardiovascular pathologies, and premature aging. Here, we report on the development of dual-targeted drugs with activity against both HIV-1 and CMV. We synthesized seven compounds that constitute conjugates of molecules that suppress both pathogens. We showed that all seven compounds exhibit low cytotoxicity and efficiently inhibited both viruses in cell lines. Furthermore, we chose a representative compound and demonstrated that it efficiently suppressed replication of HIV-1 and CMV in human lymphoid tissue ex vivo coinfected with both viruses. Further development of such compounds may lead to the development of dual-targeted anti-CMV/HIV-1 drugs. •We synthetized seven dual-targeted anti-CMV/HIV heterodimers.•AZT or 3 TC were used as anti HIV molecules while 1-[ω-(phenoxy)alkyl]uracil derivatives were used as anti CMV molecules.•These compounds inhibited CMV and HIV respectively in WS1 and MT-4 cell cultures.•Both AZT and 3 TC-based heterodimers inhibited CMV and HIV replication in coinfected human lymphoid tissues.
ISSN:0300-9084
1638-6183
DOI:10.1016/j.biochi.2021.06.011