Potent and Orally Bioavailable HIV-1 Proteinase Inhibitors Containing the 2-aminobenzylstatine Moiety

1995 ◽  
Vol 6 (5) ◽  
pp. 327-336 ◽  
Author(s):  
A. Billich ◽  
D. Scholz ◽  
B. Charpiot ◽  
H. Gstach ◽  
P. Lehr ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Proteinase Inhibitor ◽  
Proteinase Inhibitors ◽  
Infected Cells ◽  
Orally Bioavailable ◽  
Derivatives Of ◽  
Hiv 1 ◽  
Good Oral Bioavailability

In order to design HIV proteinase inhibitors which combine antiviral potency in HIV-infected cells with good oral bioavailability, new derivatives of 2-aminobenzylstatine containing HIV-1 proteinase inhibitors were synthesized. Compounds showing the desired profile emerged from a series of modifications at the P3′ moiety of the parent inhibitor [1], and are characterized by the presence of hydroxy or methoxy substituents at the C-terminal benzylamide. The most potent congeners, compounds [15] and [19], were evaluated in more detail and proved inhibitory to HIV-1 replication in primary T4 lymphocytes with EC90 = 2.2 and 2.7 nM, respectively. They also exhibited adequate oral bioavailability in the range of [13] to 42% in mice and rats. Thus, further investigation of this type of HIV proteinase inhibitor seems warranted.

Antiviral Properties of the HIV-1 Proteinase Inhibitor RO 31-8959

1994 ◽  
Vol 5 (1) ◽  
pp. 43-45 ◽  
Author(s):  
S. Galpin ◽  
N. A. Roberts ◽  
T. O'Connor ◽  
D. J. Jeffries ◽  
D. Kinchington
Keyword(s):  
Antiviral Activity ◽  
Proteinase Inhibitor ◽  
Potent Inhibitor ◽  
Significant Loss ◽  
Infectious Dose ◽  
Culture Time ◽  
Infected Cells ◽  
Resistant Strains ◽  
Peptide Derivative ◽  
Hiv 1

The peptide derivative Ro 31-8959 has been shown to be a potent inhibitor of HIV proteinase with an IC50 of 2 × 10−9M, against HIV-1RF in acutely infected lymphoblastoid cells. This inhibition was not overcome by increasing the infectious dose or by extending the culture time. Similar antiviral activity was also obtained against HIV-2, SIV and several AZT-resistant strains of HIV-1. The time of addition of the inhibitor could be delayed for 22 h without significant loss of activity, supporting its mode of action as taking place late in the replication cycle of HIV-1. Ro 31-8959 also showed activity against chronically infected cells.

scholarly journals Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity

2020 ◽  
Author(s):  
Robert T. Schooley ◽  
Aaron F. Carlin ◽  
James R. Beadle ◽  
Nadejda Valiaeva ◽  
Xing-Quan Zhang ◽  
...  
Keyword(s):  
Early Treatment ◽  
Oral Bioavailability ◽  
Advanced Disease ◽  
Metabolic Activation ◽  
Single Step ◽  
Hospitalized Patients ◽  
Activation Pathway ◽  
Clinical Recovery ◽  
Infected Cells ◽  
Orally Bioavailable

ABSTRACTThe FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cells

scholarly journals Anti-HIV-1 Activity and Structure-Activity Relationship of Cepharanoline Derivatives in Chronically Infected Cells

2001 ◽  
Vol 12 (5) ◽  
pp. 307-312 ◽  
Author(s):  
M Baba ◽  
M Okamoto ◽  
N Kashiwaba ◽  
M Ono
Keyword(s):  
Nuclear Factor Κb ◽  
Inhibitory Effects ◽  
Potent Inducer ◽  
Alkyl Derivatives ◽  
Inhibit Tumour Necrosis Factor ◽  
Infected Cells ◽  
Factor Α ◽  
Relationship Of ◽  
Derivatives Of ◽  
Hiv 1

Cepharanthine (12- O-methyl cepharanoline) is a plant alkaloid and has been shown to inhibit tumour necrosis factor-α- or phorbol 12-myristate 13-acetate-induced HIV-1 replication in the chronically infected promonocytic cell line, U1. Its mechanism of action is considered to be the inhibition of nuclear factor κB, a potent inducer of HIV-1 gene expression. In this study, we have synthesized 96 derivatives of cepharanoline, including cepharanthine, and examined their inhibitory effects on HIV-1 replication in U1 cells. Among the 12- O-alkyl derivatives, cepharanthine proved to be the most active, and the activity decreased as the length of the alkyl chain increased. All of the 12- O-acyl derivatives were totally inactive, while a few 12- O-carbamoyl derivatives displayed modest activity. Since 12- O-ethyl derivatives were found to be as active as cepharanthine against HIV-1 replication, we further synthesized various 12- O-ethyl derivatives of cepharanoline. Among the derivatives, five proved to be more active inhibitors than cepharanthine, and the most active compound was 12- O-ethylpiperazinyl cepharanoline. The 50% effective concentrations of this compound and cepharanthine were 0.0041 and 0.028 μg/ml (0.0060 and 0.046 μM), respectively.

Preparation of Chloro and Sulfanyl Derivatives of 1-(2-Deoxy-4-C-hydroxymethyl-α-L-threo-Pentofuranosyl)uracil

1997 ◽  
Vol 62 (7) ◽  
pp. 1114-1127 ◽  
Author(s):  
Hubert Hřebabecký ◽  
Jan Balzarini ◽  
Antonín Holý
Keyword(s):  
Nucleophilic Substitution ◽  
Hydrogen Chloride ◽  
Thionyl Chloride ◽  
Sodium Methoxide ◽  
Thioacetic Acid ◽  
Uracil Derivatives ◽  
Derivatives Of ◽  
Hiv 1

3'-Chloro and 3'-acetylsulfanyl derivatives of 1-(2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil were prepared by reaction of 2,3'-anhydro-1-{5'-O-benzoyl-4'-C-[(benzoyloxy)methyl]-2'-deoxy-α-L-erythro-pentofuranosyl}uracil (3) with hydrogen chloride and thioacetic acid, respectively. The reaction with hydrogen chloride gave a mixture of N-1 and N-3 substituted uracil derivatives 12 and 14. Reaction of 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-α-L-threo-pentofuranosyl}uracil (7) with thionyl chloride and subsequent debenzoylation afforded 1-(4-C-chloromethyl-2-deoxy-β-D-erythro-pentofuranosyl)uracil (19). Nucleophilic substitution with lithium thioacetate, followed by deacylation, converted 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (9) into 1-(2-deoxy-4-C-sulfanylmethyl-β-D-erythro-pentofuranosyl)uracil (21). The obtained thiols were oxidized with iodine or air to give 1,1'-[disulfandiylbis(2,3-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-3,1-diyl]di(pyrimidine-2,4-(1H,3H)-dione) (17) and 1,1'-[disulfandiylbis(2,5-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-5,1-diyl]di(pyrimidine-2,4(1H,3H)-dione) (22). Reaction of 1-{3-acetylsulfanyl-5-O-methanesulfonyl-4-C-[(benzoyloxy)methyl]-2,3-dideoxy-α-L-threo-pentofuranosyl)}uracil (24) with methanolic sodium methoxide afforded 1-(3,5-anhydro-2,3-dideoxy-4-C-hydroxymethyl-3-sulfanyl-α-L-threo-pentofuranosyl)uracil (25). The same reagent was used in the preparation of 1-(3,5-anhydro-2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil (26) from 1-{4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (8). From the series of 4'-substituted 2'-deoxyuridine derivatives, synthesized in this study, solely the 4'-chloromethyl derivative 19 and the oxetane derivative 26 exhibited an appreciable activity against HIV-1 and HIV-2.

scholarly journals 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

1997 ◽  
Vol 41 (5) ◽  
pp. 1082-1093 ◽  
Author(s):  
S M Daluge ◽  
S S Good ◽  
M B Faletto ◽  
W H Miller ◽  
M H St Clair ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Oral Bioavailability ◽  
Human Peripheral Blood ◽  
Cross Resistance ◽  
Immunodeficiency Virus ◽  
Carbocyclic Nucleoside ◽  
Hiv 1 ◽  
In Cells

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

scholarly journals Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1798
Author(s):  
Grant R. Campbell ◽  
Stephen A. Spector
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Functional Cure ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a “functional cure” where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission—a “block and lock” approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.

scholarly journals PCIP-seq: simultaneous sequencing of integrated viral genomes and their insertion sites with long reads

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Maria Artesi ◽  
Vincent Hahaut ◽  
Basiel Cole ◽  
Laurens Lambrechts ◽  
Fereshteh Ashrafi ◽  
...  
Keyword(s):  
Viral Genome ◽  
Clonal Expansion ◽  
Endogenous Retroviruses ◽  
Viral Genomes ◽  
Short Read Sequencing ◽  
Long Reads ◽  
Infected Cells ◽  
Insertion Sites ◽  
Viral Insertion ◽  
Hiv 1

AbstractThe integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus.

scholarly journals Extended Interactions between HIV-1 Viral RNA and tRNALys3 Are Important to Maintain Viral RNA Integrity

2020 ◽  
Vol 22 (1) ◽  
pp. 58
Author(s):  
Thomas Gremminger ◽  
Zhenwei Song ◽  
Juan Ji ◽  
Avery Foster ◽  
Kexin Weng ◽  
...  
Keyword(s):  
Reverse Transcription ◽  
Potential Interaction ◽  
Viral Rna ◽  
Primer Binding Site ◽  
Rna Integrity ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Extended Interaction ◽  
Hiv 1

The reverse transcription of the human immunodeficiency virus 1 (HIV-1) initiates upon annealing of the 3′-18-nt of tRNALys3 onto the primer binding site (PBS) in viral RNA (vRNA). Additional intermolecular interactions between tRNALys3 and vRNA have been reported, but their functions remain unclear. Here, we show that abolishing one potential interaction, the A-rich loop: tRNALys3 anticodon interaction in the HIV-1 MAL strain, led to a decrease in viral infectivity and reduced the synthesis of reverse transcription products in newly infected cells. In vitro biophysical and functional experiments revealed that disruption of the extended interaction resulted in an increased affinity for reverse transcriptase (RT) and enhanced primer extension efficiency. In the absence of deoxyribose nucleoside triphosphates (dNTPs), vRNA was degraded by the RNaseH activity of RT, and the degradation rate was slower in the complex with the extended interaction. Consistently, the loss of vRNA integrity was detected in virions containing A-rich loop mutations. Similar results were observed in the HIV-1 NL4.3 strain, and we show that the nucleocapsid (NC) protein is necessary to promote the extended vRNA: tRNALys3 interactions in vitro. In summary, our data revealed that the additional intermolecular interaction between tRNALys3 and vRNA is likely a conserved mechanism among various HIV-1 strains and protects the vRNA from RNaseH degradation in mature virions.

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