The Effect of Absolute Configuration on the Anti-HIV and Anti-HBV Activity of Nucleoside Analogues

1995 ◽  
Vol 6 (6) ◽  
pp. 345-355 ◽  
Author(s):  
P. A. Furman ◽  
J. E. Wilson ◽  
J. E. Reardon ◽  
G. R. Painter
Keyword(s):  
Dna Polymerase ◽  
Potent Inhibitor ◽  
Hbv Dna ◽  
The Other ◽  
Nucleoside Analogues ◽  
Differential Inhibition ◽  
Hiv Reverse Transcriptase ◽  
Hiv Rt ◽  
Anti Hiv ◽  
Selective Activity

This review concerns the effect of stereoisomerism on the selective activity of anti-HIV and anti-HBV nucleoside analogues. The synthesis of a number of nucleoside analogues with anti-HIV and anti-HBV activity yields mixtures of 1-β-D and 1-β-L stereoisomers. Anti-HIV and anti-HBV activity is associated primarily with one of the two enantiomers and the more potent activity does not always reside with the 1-β-D configuration characteristic of natural nucleosides. In the case of HIV, the origin of this stereoselectivity appears to be the result of differential metabolism of the analogues and not due to differential inhibition of the target enzyme; the HIV reverse transcriptase. However, mutations at position 184 of the HIV-RT does result in stereoselective inhibition of the enzyme. On the other hand, with HBV, there is also a stereoselective inhibition of the HBV DNA polymerase, where the 5′-triphosphate of the 1-β-L enantiomer is the more potent inhibitor.

scholarly journals Exploring New Scaffolds for the Dual Inhibition of HIV-1 RT Polymerase and Ribonuclease Associated Functions

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3821
Author(s):  
Rita Meleddu ◽  
Angela Corona ◽  
Simona Distinto ◽  
Filippo Cottiglia ◽  
Serenella Deplano ◽  
...  
Keyword(s):  
Single Agent ◽  
Hiv Reverse Transcriptase ◽  
Substitution Pattern ◽  
Associated Functions ◽  
Dual Inhibition ◽  
Hiv Rt ◽  
Therapeutic Protocols ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Selection Of

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (EMAC2063) was the most potent towards RNaseH (IC50 = 4.5 mM)- and RDDP (IC50 = 8.0 mM) HIV RT-associated functions.

scholarly journals Repurposing Multi-Targeting Plant Natural Product Scaffolds In Silico Against SARS-CoV-2 Non-Structural Proteins Implicated in Viral Pathogenesis

2021 ◽  
Author(s):  
Von Novi de Leon ◽  
Joe Anthony Manzano ◽  
Delfin Yñigo H. Pilapil ◽  
Rey Arturo T. Fernandez ◽  
James Kyle Ching ◽  
...  
Keyword(s):  
In Silico ◽  
Structural Proteins ◽  
Treatment Gap ◽  
Hiv Reverse Transcriptase ◽  
Pomolic Acid ◽  
Absorptive Property ◽  
Hiv Rt ◽  
Key Sites ◽  
Inhibitory Potential ◽  
Anti Hiv

<p>Background: Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. Thus, this study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting <i>in silico</i> key sites in the structures of SARS-CoV-2 nsps. Moreover, structures of the anti-HIV compounds were considered for druggability and toxicity. 104 anti-HIV phytochemicals were subjected to molecular docking with papain-like protease (nsp3), 3-chymotrypsin-like protease (nsp5), RNA-dependent RNA polymerase (nsp12), helicase (nsp13), SAM-dependent 2’-<i>O-</i>methyltransferase (nsp16) and its cofactor (nsp10), and endoribonuclease (nsp15). Drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top ten compounds per nsp were predicted using SwissADME. Their toxicity was also determined using OSIRIS Property Explorer.</p> <p>Results: Among the twenty-seven top-scoring compounds, the polyphenolic natural products amentoflavone (<b>1</b>), robustaflavone (<b>4</b>), punicalin (<b>9</b>), volkensiflavone (<b>11</b>), rhusflavanone (<b>13</b>), morelloflavone (<b>14</b>), hinokiflavone (<b>15</b>), and michellamine B (<b>19</b>) were multi-targeting and had the strongest affinities to at least two of the nsps (Binding Energy = -7.7 to -10.8 kcal/mol). Friedelin (<b>2</b>), pomolic acid (<b>5</b>), ursolic acid (<b>10</b>), garcisaterpenes A (<b>12</b>), hinokiflavone (<b>15</b>), and digitoxigenin-3-<i>O-</i>glucoside (<b>17</b>) were computationally druggable. Moreover, compounds <b>5</b> and <b>17</b> showed good gastrointestinal absorptive property. Most of the compounds were also predicted to be non-toxic.</p> <p>Conclusions: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 nsp3, 5, 10, 12, 13, 15, and 16, and can therefore be used as prototypes for anti-COVID-19 drug design.</p>

scholarly journals Repurposing Multi-Targeting Plant Natural Product Scaffolds In Silico Against SARS-CoV-2 Non-Structural Proteins Implicated in Viral Pathogenesis

2021 ◽  
Author(s):  
Von Novi de Leon ◽  
Joe Anthony Manzano ◽  
Delfin Yñigo H. Pilapil ◽  
Rey Arturo T. Fernandez ◽  
James Kyle Ching ◽  
...  
Keyword(s):  
In Silico ◽  
Structural Proteins ◽  
Treatment Gap ◽  
Hiv Reverse Transcriptase ◽  
Pomolic Acid ◽  
Absorptive Property ◽  
Hiv Rt ◽  
Key Sites ◽  
Inhibitory Potential ◽  
Anti Hiv

<p>Background: Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. Thus, this study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting <i>in silico</i> key sites in the structures of SARS-CoV-2 nsps. Moreover, structures of the anti-HIV compounds were considered for druggability and toxicity. 104 anti-HIV phytochemicals were subjected to molecular docking with papain-like protease (nsp3), 3-chymotrypsin-like protease (nsp5), RNA-dependent RNA polymerase (nsp12), helicase (nsp13), SAM-dependent 2’-<i>O-</i>methyltransferase (nsp16) and its cofactor (nsp10), and endoribonuclease (nsp15). Drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top ten compounds per nsp were predicted using SwissADME. Their toxicity was also determined using OSIRIS Property Explorer.</p> <p>Results: Among the twenty-seven top-scoring compounds, the polyphenolic natural products amentoflavone (<b>1</b>), robustaflavone (<b>4</b>), punicalin (<b>9</b>), volkensiflavone (<b>11</b>), rhusflavanone (<b>13</b>), morelloflavone (<b>14</b>), hinokiflavone (<b>15</b>), and michellamine B (<b>19</b>) were multi-targeting and had the strongest affinities to at least two of the nsps (Binding Energy = -7.7 to -10.8 kcal/mol). Friedelin (<b>2</b>), pomolic acid (<b>5</b>), ursolic acid (<b>10</b>), garcisaterpenes A (<b>12</b>), hinokiflavone (<b>15</b>), and digitoxigenin-3-<i>O-</i>glucoside (<b>17</b>) were computationally druggable. Moreover, compounds <b>5</b> and <b>17</b> showed good gastrointestinal absorptive property. Most of the compounds were also predicted to be non-toxic.</p> <p>Conclusions: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 nsp3, 5, 10, 12, 13, 15, and 16, and can therefore be used as prototypes for anti-COVID-19 drug design.</p>

scholarly journals Kinetic Interaction of the Diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and Other anti-HIV Active Purine Congeners with HIV Reverse Transcriptase and Human DNA Polymerases α, β and γ

1995 ◽  
Vol 6 (4) ◽  
pp. 217-221 ◽  
Author(s):  
J. M. Cherrington ◽  
S. J. W. Allen ◽  
N. Bischofberger ◽  
M. S. Chen
Keyword(s):  
Reverse Transcriptase ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Inhibitory Effects ◽  
Hiv Reverse Transcriptase ◽  
Dna Polymerase Β ◽  
Human Dna ◽  
Dna Template ◽  
Anti Hiv ◽  
Micromolar Range

The inhibitory effects of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its analogues on HIV reverse transcriptase and human DNA polymerases α, β, and γ have been studied. The analogues investigated are the diphosphates of 9-(2-phosphonylmethoxypropyl)adenine (PMPApp), 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine (PMPDAPpp), and (2R,5R)-9-[2,5-dihydro-5-(phosphonyl methoxy)-2-furanyl]adenine (D4APpp). These four compounds are much more inhibitory to HIV reverse transcriptase when an RNA template rather than a DNA template is used. The Ki, values for the four compounds range from 11 to 22 nM with an RNA template. The Ki, values for ddCTP and AZTTP are 54 nM and 8 nM, respectively. PMEApp and its analogues show varying degrees of inhibition of the human DNA polymerases. The Ki, values for PMEApp, PMPApp and PMPDAPpp against DNA polymerase α are in the micromolar range, while D4APpp is a poor inhibitor of this enzyme with a Ki, value of 65.9 μM. The inhibition of DNA polymerase β by PMEApp, PMPApp and D4APpp is minimal, while PMPDAPpp shows higher inhibition of DNA polymerase β with a Ki, value of 9.71 μM. The Ki, values for PMEApp and D4APpp against DNA polymerase γ are submicromolar, while PMPApp and PMPDAPpp are much less inhibitory to this enzyme. For comparison, ddCTP was found to be a more potent inhibitor of DNA polymerases β and γ than the diphosphates of PMEA and its analogues.

PASS-based approach to predict HIV-1 reverse transcriptase resistance

2017 ◽  
Vol 15 (02) ◽  
pp. 1650040 ◽  
Author(s):  
Olga Tarasova ◽  
Dmitry Filimonov ◽  
Vladimir Poroikov
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Open Data ◽  
Amino Acid Substitutions ◽  
Hiv Reverse Transcriptase ◽  
Hiv Rt ◽  
Hiv Drugs ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Hiv 1

HIV reverse transcriptase (RT) inhibitors targeting the early stages of virus–host interactions are of great interest to scientists. Acquired HIV RT resistance happens due to mutations in a particular region of the pol gene encoding the HIV RT amino acid sequence. We propose an application of the previously developed PASS algorithm for prediction of amino acid substitutions potentially involved in the resistance of HIV-1 based on open data. In our work, we used more than 3200 HIV-1 RT variants from the publicly available Stanford HIV RT and protease sequence database already tested for 10 anti-HIV drugs including both nucleoside and non-nucleoside RT inhibitors. We used a particular amino acid residue and its position to describe primary structure-resistance relationships. The average balanced accuracy of the prediction obtained in 20-fold cross-validation for the Phenosense dataset was about 88% and for the Antivirogram dataset was about 79%. Thus, the PASS-based algorithm may be used for prediction of the amino acid substitutions associated with the resistance of HIV-1 based on open data. The computational approach for the prediction of HIV-1 associated resistance can be useful for the selection of RT inhibitors for the treatment of HIV infected patients in the clinical practice. Prediction of the HIV-1 RT associated resistance can be useful for the development of new anti-HIV drugs active against the resistant variants of RT. Therefore, we propose that this study can be potentially useful for anti-HIV drug development.

scholarly journals Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1718 ◽  
Author(s):  
Roberto Romeo ◽  
Daniela Iannazzo ◽  
Lucia Veltri ◽  
Bartolo Gabriele ◽  
Beatrice Macchi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Nucleoside Analogs ◽  
Hiv Reverse Transcriptase ◽  
Inhibitor Activity ◽  
Virus Activity ◽  
Immunodeficiency Virus ◽  
Hiv Rt ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Nanomolar Range

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a–c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV.

scholarly journals Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89.

1997 ◽  
Vol 41 (5) ◽  
pp. 1099-1107 ◽  
Author(s):  
M B Faletto ◽  
W H Miller ◽  
E P Garvey ◽  
M H St Clair ◽  
S M Daluge ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Adenosine Deaminase ◽  
Mycophenolic Acid ◽  
Potent Inhibitor ◽  
Selective Inhibitor ◽  
Hiv Reverse Transcriptase ◽  
Adenylate Deaminase ◽  
Immunodeficiency Virus ◽  
Anti Hiv

The anabolism of 1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, a selective inhibitor of human immunodeficiency virus (HIV), was characterized in human T-lymphoblastoid CD4+ CEM cells. 1592U89 was ultimately anabolized to the triphosphate (TP) of the guanine analog (-)-carbovir (CBV), a potent inhibitor of HIV reverse transcriptase. However, less than 2% of intracellular 1592U89 was converted to CBV, an amount insufficient to account for the CBV-TP levels observed. 1592U89 was anabolized to its 5'-monophosphate (MP) by the recently characterized enzyme adenosine phosphotransferase, but neither its diphosphate (DP) nor its TP was detected. The MP, DP, and TP of CBV were found in cells incubated with either 1592U89 or CBV, with CBV-TP being the major phosphorylated species. We confirmed that CBV is phosphorylated by 5'-nucleotidase and that mycophenolic acid increased the formation of CBV-TP from CBV 75-fold. However, mycophenolic acid did not stimulate 1592U89 anabolism to CBV-TP. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) did not inhibit CBV-TP formation from CBV or 1592U89, whereas the adenylate deaminase inhibitor 2'-deoxycoformycin selectively inhibited 1592U89 anabolism to CBV-TP and reversed the antiviral activity of 1592U89. 1592U89-MP was not a substrate for adenylate deaminase but was a substrate for a distinct cytosolic deaminase that was inhibited by 2'-deoxycoformycin-5'-MP. Thus, 1592U89 is phosphorylated by adenosine phosphotransferase to 1592U89-MP, which is converted by a novel cytosolic enzyme to CBV-MP. CBV-MP is then further phosphorylated to CBV-TP by cellular kinases. This unique activation pathway enables 1592U89 to overcome the pharmacokinetic and toxicological deficiencies of CBV while maintaining potent and selective anti-HIV activity.

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