RESUMO
Great pioneers of nucleic acid chemistry had elucidated nucleic acid functions and structures and developed various antiviral modified nucleoside drugs. It is possible in theory that antiviral modified nucleosides prevent viral replication by inhibiting viral polymerases. However, biological phenomena far exceed our predictions at times. We describe the characteristics of the approved antiviral modified nucleosides from an organic chemistry perspective. Also, based on our experiences and findings through the development of the HIV-1 reverse-transcriptase inhibitor "Islatravir", we provide the practical and approximate guidelines for the drug development of antiviral modified nucleosides against COVID-19.
RESUMO
Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.
Assuntos
Aminoácidos/síntese química , Inibidores da Protease de HIV/síntese química , HIV-1/efeitos dos fármacos , Fenilbutiratos/síntese química , Tiazóis/síntese química , Aminoácidos/química , Aminoácidos/farmacologia , Farmacorresistência Viral , Protease de HIV/química , Protease de HIV/genética , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , HIV-1/genética , Modelos Moleculares , Mutação , Fenilbutiratos/química , Fenilbutiratos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Cisteína/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Fenilbutiratos/síntese química , Fenilbutiratos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Amidas/química , Linhagem Celular , HIV/efeitos dos fármacos , Inibidores da Protease de HIV/química , Humanos , Modelos Moleculares , Fenilbutiratos/química , Tiazóis/químicaRESUMO
Z- and Fmoc-L-tetrahydrofuranylglycines have been obtained from L-vinylglycine through dipolar cycloaddition reaction, and its Fmoc derivative has been applied in the synthesis of modified S9 and S10 substrates of HIV-1 protease. These compounds mostly acted as strong inhibitors, rather than substrates, of the protease, probably due to the favourable interactions of the tetrahydrofuranylglycine moiety at the S(2) site.