Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Feb 15:32:116000.
doi: 10.1016/j.bmc.2021.116000. Epub 2021 Jan 8.

Design, synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors

Francesca Curreli  1 , Shahad Ahmed  1 , Sofia M Benedict Victor  1 , Ildar R Iusupov  2 , Evgeny A Spiridonov  2 , Dmitry S Belov  2 , Andrea Altieri  2 , Alexander V Kurkin  2 , Asim K Debnath  3
Affiliations

Design, synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors

Francesca Curreli et al. Bioorg Med Chem. .

Abstract

We presented our continuing stride to optimize the second-generation NBD entry antagonist targeted to the Phe43 cavity of HIV-1 gp120. We have synthesized thirty-eight new and novel analogs of NBD-14136, earlier designed based on a CH2OH "positional switch" hypothesis, and derived a comprehensive SAR. The antiviral data confirmed that the linear alcohol towards the "N" (C4) of the thiazole ring yielded more active inhibitors than those towards the "S" (C5) of the thiazole ring. The best inhibitor, NBD-14273 (compound 13), showed both improved antiviral activity and selectivity index (SI) against HIV-1HXB2 compared to NBD-14136. We also tested NBD-14273 against a large panel of 50 HIV-1 Env-pseudotyped viruses representing clinical isolates of diverse subtypes. The overall mean data indicate that antiviral potency against these isolates improved by ~3-fold, and SI also improved ~3-fold compared to NBD-14136. This new and novel inhibitor is expected to pave the way for further optimization to a more potent and clinically relevant inhibitor against HIV-1.

Keywords: Broad-spectrum; Cytotoxicity; ENV-pseudovirus; Gp120 entry-antagonist; HIV-1; Structure–activity relationship (SAR); selectivity index (SI).

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.

Figures

Figure 1.
Figure 1.
“Positional switch” hypothesis indicating no interaction of the CH2OH group at position 5 in the thiazole ring in the x-ray structure of NBD-14010 bound to HIV-1 gp120. When the CH2OH was switched to position 4 in the thiazole ring in NBD-14189, it forms H-bond (indicated by violet arrows using a glide docking pose) with Met426 and Gly431.
Figure 2.
Figure 2.. Infectivity of CD4-negative Cf2Th-CCR5 cells by CD4-dependent HIV-1ADA.
CCf2Th-CCR5 cells were infected with CD4-dependent HIV-1ADA in the presence of NBD-14273 and NBD-556, which was used as a control. The Relative virus infectivity indicates the ratio of the amount of infection detected in the presence and absence of the compounds. Three independent experiments were performed in triplicate, and the graph is representative of one experiment. The toxicity of the compounds against these cells was evaluated to calculate the CC50 values: for NBD-556, the CC50 was > 60, and for NBD-14273, it was 31.2±1.4. All the values represent the mean ± standard deviation.
Scheme 1.
Scheme 1.
Synthesis of S4a–c.
Scheme 2.
Scheme 2.
Synthesis of S5–S8.
Scheme 3.
Scheme 3.
Synthesis of S9–S14 and S21.
Scheme 4.
Scheme 4.
Synthesis of S15, S16 and S21.
Scheme 5.
Scheme 5.
Synthesis of compounds 1–38.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Caffrey M, HIV envelope: challenges and opportunities for development of entry inhibitors. Trends Microbiol. 2011, 19, 191–197. - PMC - PubMed
    1. Didigu CA; Doms RW, Novel Approaches to Inhibit HIV Entry. Viruses 2012, 4, 309–324. - PMC - PubMed
    1. Yu F; Lu L; Du L; Zhu X; Debnath AK; Jiang S, Approaches for Identification of HIV-1 Entry Inhibitors Targeting gp41 Pocket. Viruses 2013, 5, 127–149. - PMC - PubMed
    1. Lu L; Yu F; Cai L; Debnath AK; Jiang S, Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41. Curr. Top. Med. Chem 2016, 16, 1074–1090. - PMC - PubMed
    1. Duffalo ML; James CW, Enfuvirtide: a novel agent for the treatment of HIV-1 infection. Ann. Pharmacother 2003, 37 (10), 1448–1456. - PubMed

Publication types

MeSH terms