DOI QR코드

DOI QR Code

Identification of a novel type of small molecule inhibitor against HIV-1

  • Kim, Byung Soo (Avixgen Inc.) ;
  • Park, Jung Ae (Avixgen Inc.) ;
  • Kim, Min-Jung (Avixgen Inc.) ;
  • Kim, Seon Hee (National Research Laboratory of Molecular Virology, Department of Pathology, School of Medicine, The Catholic University of Korea) ;
  • Yu, Kyung Lee (National Research Laboratory of Molecular Virology, Department of Pathology, School of Medicine, The Catholic University of Korea) ;
  • You, Ji Chang (Avixgen Inc.)
  • Received : 2014.11.04
  • Accepted : 2014.11.18
  • Published : 2015.02.28

Abstract

Here we report a new chemical inhibitor against HIV-1 with a novel structure and mode of action. The inhibitor, designated as A1836, inhibited HIV-1 replication and virus production with a 50% inhibitory concentration ($IC_{50}$) of $2.0{\mu}M$ in an MT-4 cell-based and cytopathic protection antiviral assay, while its 50% cytotoxic concentration ($CC_{50}$) was much higher than $50{\mu}M$. Examination of the effect of A1836 on in vitro HIV-1 reverse transcriptase (RT) and integrase showed that neither were molecular targets of A1836. The characterization and re-infection assay of the HIV-1 virions generated in the presence of A1836 showed that the synthesis of early RT products in the cells infected with the virions was inhibited dose-dependently, due in part to abnormal protein formation within the virions, thus resulting in an impaired infectivity. These results suggest that A1836 might be a novel candidate for the development of a new type of HIV-1 inhibitor.

Keywords

References

  1. De Clercq E (1992) HIV inhibitors targeted at the reverse transcriptase. AIDS Res Hum Retroviruses 8, 119-134 https://doi.org/10.1089/aid.1992.8.119
  2. Molla A, Granneman GR, Sun E and Kempf DJ (1998) Recent developments in HIV protease inhibitor therapy. Antiviral Res 39, 1-23 https://doi.org/10.1016/S0166-3542(98)00011-4
  3. Ingale KB and Bhatia MS (2011) HIV-1 integrase inhibitors: a review of their chemical development. Antivir Chem Chemother 22, 95-105 https://doi.org/10.3851/IMP1740
  4. Ryser HJ and Flückiger R (2005) Progress in targeting HIV-1 entry. Drug Discov Today 10, 1085-1094 https://doi.org/10.1016/S1359-6446(05)03550-6
  5. Mehellou Y and De Clercq E (2010) Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go? J Med Chem 53, 521-538 https://doi.org/10.1021/jm900492g
  6. Flexner C (2007) HIV drug development: the next 25 years. Nat Rev Drug Discov 6, 959-966 https://doi.org/10.1038/nrd2336
  7. Condra JH, Schleif WA, Blahy OM et al (1995) In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 374, 569-571 https://doi.org/10.1038/374569a0
  8. Freed EO (1998) HIV-1 gag proteins: diverse functions in the virus life cycle. Virology 251, 1-15 https://doi.org/10.1006/viro.1998.9398
  9. Domagala JM, Bader JP, Gogliotti RD et al (1997) A new class of anti-HIV-1 agents targeted toward the nucleocapsid protein NCp7: the 2, 2'-dithiobisbenzamides. Bioorg Med Chem 5, 569-579 https://doi.org/10.1016/S0968-0896(96)00269-6
  10. Srivastava P, Schito M, Fattah RJ et al (2004) Optimization of unique, uncharged thioesters as inhibitors of HIV replication. Bioorg Med Chem 12, 6437-6450 https://doi.org/10.1016/j.bmc.2004.09.032
  11. Ong EB, Watanabe N, Saito A et al (2011) Vipirin, a coumarin-based HIV-1 Vpr inhibitor, interacts with a hydrophobic region of VPR. J Biol Chem 286, 14049-14056 https://doi.org/10.1074/jbc.M110.185397
  12. Dubé M, Bego MG, Paquay C and Cohen ÉA (2010) Modulation of HIV-1 host interaction: role of the Vpu accessory protein. Retrovirology 7, 144 https://doi.org/10.1186/1742-4690-7-S1-P144
  13. Li ZY, Zhan P and Liu XY (2010) Progression in the study of HIV-1 Vif and related inhibitors. Yao Xue Xue Bao 45, 684-693
  14. Kwon HS, Park JA, Kim JH and You JC (2012) Identification of anti-HIV and anti-reverse transcriptase activity from Tetracera scandens. BMB Rep 45, 165-170 https://doi.org/10.5483/BMBRep.2012.45.3.165
  15. Hayashi S, Phadtare S, Zemlicka J, Matsukura M, Mitsuya H and Broder S (1988) Adenallene and cytallene: acyclic- nucleoside analogues that inhibit replication and cytopathic effect of human immunodeficiency virus in vitro. Proc Natl Acad Sci U S A 85, 6127-6131 https://doi.org/10.1073/pnas.85.16.6127
  16. Forshey BM, von Schwedler U, Sundquist WI and Aiken C (2002) Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication. J Virol 76, 5667-5677 https://doi.org/10.1128/JVI.76.11.5667-5677.2002

Cited by

  1. Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends vol.59, pp.7, 2016, https://doi.org/10.1021/acs.jmedchem.5b00497
  2. Design, synthesis and antiviral evaluation of novel heteroarylcarbothioamide derivatives as dual inhibitors of HIV-1 reverse transcriptase-associated RNase H and RDDP functions vol.75, pp.6, 2017, https://doi.org/10.1093/femspd/ftx078
  3. Chloro-1,4-dimethyl-9H-carbazole Derivatives Displaying Anti-HIV Activity vol.23, pp.2, 2018, https://doi.org/10.3390/molecules23020286
  4. Investigation of functional roles of transcription termination factor-1 (TTF-I) in HIV-1 replication vol.51, pp.7, 2018, https://doi.org/10.5483/BMBRep.2018.51.7.032
  5. Investigation of function and regulation of the YB-1 cellular factor in HIV replication vol.51, pp.6, 2018, https://doi.org/10.5483/BMBRep.2018.51.6.231