In Vitro Evaluation of Bis-3-Chloropiperidines as RNA Modulators Targeting TAR and TAR-Protein Interaction

After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabilizing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analytical approaches for the study of multicomponent RNA-based interactions.

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In vitro Evaluation of Bis-3-chloropiperidines as RNA Modulators Targeting TAR and TAR-protein Interaction

10.20944/preprints202112.0225.v1 ◽

2021 ◽

Author(s):

Alice Sosic ◽

Giulia Olivato ◽

Caterina Carraro ◽

Richard Göttlich ◽

Dan Fabris ◽

...

Keyword(s):

Protein Interaction ◽

Chaperone Activity ◽

Next Generation ◽

Response Element ◽

In Vitro Evaluation ◽

Loop Domain ◽

Activation Response ◽

Hiv 1

After a long limbo, RNA has gained its credibility as a druggable target, fully earning its de-served role in the next-generation area of pharmaceutical R&D. We have recently probed the Trans-Activation Response element (TAR), a RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabiliz-ing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analyti-cal approaches for the study of multicomponent RNA-based interactions.

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Bis-3-Chloropiperidines Targeting TAR RNA as A Novel Strategy to Impair the HIV-1 Nucleocapsid Protein

Molecules ◽

10.3390/molecules26071874 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1874

Author(s):

Alice Sosic ◽

Giulia Olivato ◽

Caterina Carraro ◽

Richard Göttlich ◽

Dan Fabris ◽

...

Keyword(s):

Rna Sequences ◽

Protein Inhibition ◽

Rna Targeting ◽

Activation Response ◽

Tar Rna ◽

Novel Strategy ◽

Bulge Loop ◽

Targeting Strategy ◽

Hiv 1

Specific RNA sequences regulate functions essential to life. The Trans-Activation Response element (TAR) is an RNA stem–bulge–loop structure involved in several steps of HIV-1 replication. In this work, we show how RNA targeting can inhibit HIV-1 nucleocapsid (NC), a highly conserved protein known to catalyze nucleic acid melting and strand transfers during reverse transcription. Our RNA targeting strategy consists of the employment of bis-3-chloropiperidines (B-CePs) to impair RNA melting through bifunctional alkylation. Specific interactions between B-CePs and TAR RNA were analytically investigated by gel electrophoresis and mass spectrometry, allowing the elucidation of B-CePs’ recognition of TAR, and highlighting an RNA-directed mechanism of protein inhibition. We propose that B-CePs can freeze TAR tridimensional conformation, impairing NC-induced dynamics and finally inhibiting its functions in vitro.

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Synthesis of N-glyoxylyl peptides and their in vitro evaluation as HIV-1 protease inhibitors

Bioorganic & Medicinal Chemistry ◽

10.1016/s0968-0896(97)00016-3 ◽

1997 ◽

Vol 5 (4) ◽

pp. 707-714 ◽

Cited By ~ 11

Author(s):

Driss Qasmi ◽

Eve de Rosny ◽

Loïc René ◽

Bernard Badet ◽

Isabelle Vergely ◽

...

Keyword(s):

Protease Inhibitors ◽

In Vitro Evaluation ◽

Glyoxylyl Peptides ◽

Hiv 1

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Development and in vitro evaluation of chloroquine gels as microbicides against HIV-1 infection

Virology ◽

10.1016/j.virol.2008.06.005 ◽

2008 ◽

Vol 378 (2) ◽

pp. 306-310 ◽

Cited By ~ 12

Author(s):

Joachim Brouwers ◽

Kurt Vermeire ◽

Dominique Schols ◽

Patrick Augustijns

Keyword(s):

In Vitro Evaluation ◽

Hiv 1

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Development and in vitro evaluation of a vaginal microbicide gel formulation for UAMC01398, a novel diaryltriazine NNRTI against HIV-1

Antiviral Research ◽

10.1016/j.antiviral.2013.11.005 ◽

2014 ◽

Vol 101 ◽

pp. 113-121 ◽

Cited By ~ 18

Author(s):

Carolien Grammen ◽

Kevin K. Ariën ◽

Muthusamy Venkatraj ◽

Jurgen Joossens ◽

Pieter Van der Veken ◽

...

Keyword(s):

In Vitro Evaluation ◽

Vaginal Microbicide ◽

Hiv 1

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Design, Synthesis and In Vitro Evaluation of 4-Oxo-6-Substituted Phenyl- 2-Thioxo1,2,3,4-Tetrahydropyrimidine-5-Carbonitrile Derivatives as HIV Integrase Strand Transfer Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201022193325 ◽

2020 ◽

Vol 17 ◽

Author(s):

Pankaj Wadhwa ◽

Priti Jain ◽

Hemant R. Jadhav

Keyword(s):

In Silico ◽

Strand Transfer ◽

Hiv Integrase ◽

Chromosomal Dna ◽

Molecular Docking Study ◽

Design Synthesis ◽

In Vitro Evaluation ◽

Integrase Strand Transfer Inhibitors ◽

Hiv 1

Aim:: To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4- tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors. Background:: Human immunodeficiency virus-1 (HIV-1), a member of retroviridae family, is the primary causative agent of acquired immunodeficiency syndrome (AIDS). Three enzymes viz: integrase (IN), reverse transcriptase (RT) and protease play important role in its replication cycle. HIV-1 integrase is responsible for the incorporation of viral DNA into human chromosomal DNA by catalyzing two independent reactions, 3′-processing (3′-P) and strand transfer (ST), which are observed as the “point of no-return” in HIV infection. Objective:: To develop inhibitors against HIV integrase strand transfer step. Methods:: Our previous results indicated that tetrahydro pyrimidine-5-carboxamide derivatives are potent HIV-1 IN inhibitors (unpublished results from our laboratory). Taking clue from above studies and our own experience, we hypothesized 4- oxo-6-substituted phenyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues (14a to 14n) as inhibitors of HIV-1 Integrase strand transfer. As shown in figure 2, prototype compound 14 can be viewed as hybrid structure having characteristics of dihydropyrimidine derivatives 10-12 and tyrphostin 13. Result:: A total of fourteen derivatives of 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (14a-14n) were synthesized and evaluated using HIV-1 Integrase Assay Kit (Xpressbio Life Science Products, USA). The percentage inhibition of all compounds was investigated at 10 μM concentration and IC50 value of few highly active compounds was studied. The obtained results were validated by in silico molecular docking study using Glide (maestro version 9.3, Schrödinger suite) in extra precision (XP) mode. Conclusion:: Fourteen 4-oxo-6-substituted phenyl-2-thioxo 1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues were synthesized and evaluated for HIV-1 IN inhibitory activity. Three compounds 14a, 14e, and 14h exhibited significant percentage inhibition of HIV-1 IN. There was good in vitro - in silico correlation. However, none of the derivative was active against HIV-1 and HIV-2 below their cytotoxic concentration. It needs to be seen whether these compounds can be explored further for their anti-HIV or cytotoxic potential.

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In vitro Evaluation of the antiviral effects of acemannan on the replication and pathogenesis of HIV-1 and other enveloped viruses: Modification of the processing of glycoprotein precursors

Antiviral Research ◽

10.1016/0166-3542(90)90156-2 ◽

1990 ◽

Vol 13 ◽

pp. 83 ◽

Cited By ~ 7

Keyword(s):

In Vitro Evaluation ◽

Enveloped Viruses ◽

Antiviral Effects ◽

Hiv 1

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Molecular cloning and in vitro evaluation of an infectious simian-human immunodeficiency virus containing env of a primary Chinese HIV-1 subtype C isolate

Journal of Medical Primatology ◽

10.1111/j.1600-0684.2005.00098.x ◽

2005 ◽

Vol 34 (2) ◽

pp. 101-107 ◽

Cited By ~ 8

Author(s):

YingYun Wu ◽

KunXue Hong ◽

Agnes-Laurence Chenine ◽

James B. Whitney ◽

QiMin Chen ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Molecular Cloning ◽

Subtype C ◽

In Vitro Evaluation ◽

Immunodeficiency Virus ◽

Hiv 1

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TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00986-09 ◽

2009 ◽

Vol 54 (2) ◽

pp. 718-727 ◽

Cited By ~ 203

Author(s):

Hilde Azijn ◽

Ilse Tirry ◽

Johan Vingerhoets ◽

Marie-Pierre de Béthune ◽

Guenter Kraus ◽

...

Keyword(s):

Reverse Transcriptase ◽

Transcriptase Inhibitor ◽

Screening Strategy ◽

Cross Resistance ◽

Next Generation ◽

Wild Type ◽

Genetic Barrier ◽

Nnrti Resistance ◽

Hiv 1

ABSTRACT Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50 values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50 values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant. In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. These in vitro analyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.

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