scholarly journals Pharmacotherapy Update: Treatment of HIV Infection with Darunavir

2010 ◽  
Vol 2 ◽  
pp. CMT.S1101
Author(s):  
A. Viganò ◽  
V. Manfredini ◽  
C. Mameli ◽  
V. Giacomet ◽  
G.V. Zuccotti
Keyword(s):  
Protease Inhibitor ◽  
Pharmacokinetic Profile ◽  
Hepatic Function ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Drug Concentrations ◽  
Function Impairment ◽  
Age Range ◽  
Hiv 1 ◽  
Antiretroviral Activity

Darunavir is an oral peptidomimetic HIV-1 protease inhibitor with antiretroviral activity against wild type HIV strains and HIV strains with protease inhibitor mutations. Ritonavir-boosted darunavir is rapidly absorbed and it has a higher bioavailability than unboosted darunavir. In HIV infected adults, the pharmacokinetic profile of darunavir showed that the drug concentrations are similar in the age range between 18 to 65 years and unaffected by the presence of moderate renal or hepatic function impairment. Darunavir chemical structure provides a strong interaction between the drug and HIV-1 protease and accounts for its potent antiretroviral activity and high genetic barrier to the development of resistance. The efficacy, safety and tolerability of darunavir have been widely demonstrated in HIV-infected treatment-experienced and naïve adult patients and it's use has been labelled in this population. Recently, upon the approval of the Food and Drug Administration, a 75 mg darunavir's tablet formulation has been licensed for the treatment of HIV-infected children and adolescents in the age range between 6 to 17 years.

scholarly journals TMC125 Displays a High Genetic Barrier to the Development of Resistance: Evidence from In Vitro Selection Experiments

2005 ◽  
Vol 79 (20) ◽  
pp. 12773-12782 ◽  
Author(s):  
Johan Vingerhoets ◽  
Hilde Azijn ◽  
Els Fransen ◽  
Inky De Baere ◽  
Liesbet Smeulders ◽  
...  
Keyword(s):  
Wild Type Virus ◽  
Cross Resistance ◽  
Resistant Virus ◽  
Wild Type ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Selection Experiments ◽  
The Impact ◽  
Hiv 1

ABSTRACT TMC125 is a potent new investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that is active against human immunodeficiency virus type 1 (HIV-1) with resistance to currently licensed NNRTIs. Sequential passage experiments with both wild-type virus and NNRTI-resistant virus were performed to identify mutations selected by TMC125 in vitro. In addition to “classic” selection experiments at a low multiplicity of infection (MOI) with increasing concentrations of inhibitors, experiments at a high MOI with fixed concentrations of inhibitors were performed to ensure a standardized comparison between TMC125 and current NNRTIs. Both low- and high-MOI experiments demonstrated that the development of resistance to TMC125 required multiple mutations which frequently conferred cross-resistance to efavirenz and nevirapine. In high-MOI experiments, 1 μM TMC125 completely inhibited the breakthrough of resistant virus from wild-type and NNRTI-resistant HIV-1, in contrast to efavirenz and nevirapine. Furthermore, breakthrough of virus from site-directed mutant (SDM) SDM-K103N/Y181C occurred at the same time or later with TMC125 as breakthrough from wild-type HIV-1 with efavirenz or nevirapine. The selection experiments identified mutations selected by TMC125 that included known NNRTI-associated mutations L100I, Y181C, G190E, M230L, and Y318F and the novel mutations V179I and V179F. Testing the antiviral activity of TMC125 against a panel of SDMs indicated that the impact of these individual mutations on resistance was highly dependent upon the presence and identity of coexisting mutations. These results demonstrate that TMC125 has a unique profile of activity against NNRTI-resistant virus and possesses a high genetic barrier to the development of resistance in vitro.

scholarly journals Genetic barrier to the development of resistance to rilpivirine and etravirine between HIV-1 subtypes CRF02_AG and B

2013 ◽  
Vol 68 (11) ◽  
pp. 2515-2520 ◽  
Author(s):  
D. B. Fofana ◽  
C. Soulie ◽  
A. I. Maiga ◽  
S. Fourati ◽  
I. Malet ◽  
...  
Keyword(s):  
Genetic Barrier ◽  
Development Of Resistance ◽  
Hiv 1

Genetic Barrier to the Development of Resistance to Integrase Inhibitors in HIV-1 Subtypes CRF01_AE and B

Intervirology ◽  
2012 ◽  
Vol 55 (4) ◽  
pp. 103-111 ◽  
Author(s):  
Hai Le Nguyen ◽  
Kiat Ruxrungtham ◽  
Constance Delaugerre
Keyword(s):  
Integrase Inhibitors ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Hiv 1

scholarly journals A Modified P1 Moiety Enhancesin vitroAntiviral Activity against Various Multi-Drug-Resistant HIV-1 Variants andin vitroCNS Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413

2016 ◽  
pp. AAC.01428-16 ◽  
Author(s):  
Masayuki Amano ◽  
Pedro Miguel Salcedo-Gómez ◽  
Rui Zhao ◽  
Ravikiran S. Yedidi ◽  
Debananda Das ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
System Analysis ◽  
Hydrophobic Surface ◽  
Drug Resistant ◽  
Highly Active ◽  
Development Of Resistance ◽  
Strong Antiviral Activity ◽  
Cns Penetration ◽  
Hiv 1

We here report that GRL-10413, a novel non-peptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (EC50: 0.00035 - 0.0018 μM) with minimal cytotoxicity (CC50: 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1NL4-3variants selected by up to 5 μM concentrations of atazanavir, lopinavir, or amprenavir (EC50: 0.0021 - 0.0023 μM). GRL-10413 also maintained its strong antiviral activity against multi-drug-resistant clinical HIV-1 variants isolated from patients, who no longer responded to various antiviral regimens after long-term antiretroviral therapy. The development of resistance against GRL-10413 was significantly delayed compared to that of APV. In addition, GRL-10413 showed a favorable central nervous system (CNS) penetration property as assessed with anin vitroblood brain barrier (BBB) reconstruction system. Analysis of the crystal structure of HIV-1 protease in complex with GRL-10413 demonstrated that the modified P1 moiety of GRL-10413 has a greater hydrophobic surface area and makes greater van der Waals contacts with active-site amino acids of protease than in the case of darunavir. Moreover, the chlorine substituent in the P1 moiety interacts with protease in two distinct configurations. The present data demonstrate that GRL-10413 has desirable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1 variants with favorable CNS-penetration capability and that the newly modified P1-moiety may confer desirable features in designing novel anti-HIV-1 PIs.

scholarly journals GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 VariantsIn Vitro

2013 ◽  
Vol 57 (5) ◽  
pp. 2036-2046 ◽  
Author(s):  
Masayuki Amano ◽  
Yasushi Tojo ◽  
Pedro Miguel Salcedo-Gómez ◽  
Joseph Richard Campbell ◽  
Debananda Das ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serum Proteins ◽  
Wide Spectrum ◽  
Hiv Protease ◽  
Active Site Residues ◽  
Development Of Resistance ◽  
Immunodeficiency Virus ◽  
Protease Substrate ◽  
Binding Pockets ◽  
Hiv 1

ABSTRACTWe report that GRL-0519, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containingtris-tetrahydrofuranylurethane (tris-THF) and a sulfonamide isostere, is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0005 to 0.0007 μM) with minimal cytotoxicity (50% cytotoxic concentration [CC50], 44.6 μM). GRL-0519 blocked the infectivity and replication of HIV-1NL4-3variants selected by up to a 5 μM concentration of ritonavir, lopinavir, or atazanavir (EC50, 0.0028 to 0.0033 μM). GRL-0519 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, highly darunavir (DRV)-resistant variants, and HIV-2ROD. The development of resistance against GRL-0519 was substantially delayed compared to other PIs, including amprenavir (APV) and DRV. The effects of nonspecific binding of human serum proteins on GRL-0519's antiviral activity were insignificant. Our analysis of the crystal structures of GRL-0519 (3OK9) and DRV (2IEN) with protease suggested that thetris-THF moiety, compared to thebis-THF moiety present in DRV, has greater water-mediated polar interactions with key active-site residues of protease and that thetris-THF moiety and paramethoxy group effectively fill the S2 and S2′ binding pockets, respectively, of the protease. The present data demonstrate that GRL-0519 has highly favorable features as a potential therapeutic agent for treating patients infected with wild-type and/or multi-PI-resistant variants and that thetris-THF moiety is critical for strong binding of GRL-0519 to the HIV protease substrate binding site and appears to be responsible for its favorable antiretroviral characteristics.

scholarly journals A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Manabu Aoki ◽  
Hironori Hayashi ◽  
Kalapala Venkateswara Rao ◽  
Debananda Das ◽  
Nobuyo Higashi-Kuwata ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protease Inhibitor ◽  
Halogen Bond ◽  
Cellular Growth ◽  
Drug Resistant ◽  
Genetic Barrier ◽  
Central Nervous System Penetration ◽  
Ic50 Values ◽  
Hiv 1

Antiretroviral therapy for HIV-1 infection/AIDS has significantly extended the life expectancy of HIV-1-infected individuals and reduced HIV-1 transmission at very high rates. However, certain individuals who initially achieve viral suppression to undetectable levels may eventually suffer treatment failure mainly due to adverse effects and the emergence of drug-resistant HIV-1 variants. Here, we report GRL-142, a novel HIV-1 protease inhibitor containing an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran, which has extremely potent activity against all HIV-1 strains examined with IC50 values of attomolar-to-picomolar concentrations, virtually no effects on cellular growth, extremely high genetic barrier against the emergence of drug-resistant variants, and favorable intracellular and central nervous system penetration. GRL-142 forms optimum polar, van der Waals, and halogen bond interactions with HIV-1 protease and strongly blocks protease dimerization, demonstrating that combined multiple optimizing elements significantly enhance molecular and atomic interactions with a target protein and generate unprecedentedly potent and practically favorable agents.

scholarly journals Ibalizumab, a Novel Monoclonal Antibody for the Management of Multidrug-Resistant HIV-1 Infection

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Mario V. Beccari ◽  
Bryan T. Mogle ◽  
Eric F. Sidman ◽  
Keri A. Mastro ◽  
Elizabeth Asiago-Reddy ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Mechanism Of Action ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Pharmacokinetic Parameters ◽  
Glycosylation Sites ◽  
Humanized Monoclonal Antibody ◽  
Resistance Data ◽  
Hiv 1 ◽  
Antiretroviral Activity

ABSTRACT Limited antiretrovirals are currently available for the management of multidrug-resistant (MDR) HIV-1 infection. Ibalizumab, a recombinant humanized monoclonal antibody, represents the first novel agent for HIV-1 management in over a decade and is the first monoclonal antibody for the treatment of MDR HIV-1 infection in combination with other forms of antiretroviral therapy in heavily treatment-experienced adults who are failing their current antiretroviral regimen. Ibalizumab demonstrates a novel mechanism of action as a CD4-directed postattachment inhibitor and has a favorable pharmacokinetic profile that allows for a dosing interval of every 14 days after an initial loading dose. Clinical studies have demonstrated reasonably substantial antiretroviral activity with ibalizumab among a complex patient population with advanced HIV-1 infection who are receiving an optimized background regimen, where limited therapeutic options exist. Ibalizumab was well tolerated in clinical trials, and the most common adverse effects included diarrhea, nausea, dizziness, fatigue, pyrexia, and rash. Resistance to ibalizumab has also been observed via reduced expression or loss of the potential N-linked glycosylation sites in the V5 loop of the envelope glycoprotein 120. The mechanism of action, pharmacokinetic parameters, efficacy, and safety of ibalizumab present an advance in the management of MDR HIV-1 infection. Future studies and postmarketing experience will further determine longer-term clinical efficacy, safety, and resistance data for ibalizumab.

scholarly journals A novel HIV-1 protease inhibitor, GRL-044, has potent activity against various HIV-1s with an extremely high genetic barrier to the emergence of HIV-1 drug resistance

2019 ◽  
Vol 1 (1) ◽  
pp. 36-48 ◽  
Author(s):  
Manabu Aoki ◽  
Simon B. Chang ◽  
Debananda Das ◽  
Cuthbert Martyr ◽  
Nicole S. Delino ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitor ◽  
Genetic Barrier ◽  
Hiv 1

scholarly journals Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

2016 ◽  
Vol 113 (19) ◽  
pp. 5388-5393 ◽  
Author(s):  
Annalaura Brai ◽  
Roberta Fazi ◽  
Cristina Tintori ◽  
Claudio Zamperini ◽  
Francesca Bugli ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Host Factor ◽  
Human Pathogens ◽  
Genetic Barrier ◽  
Dna And Rna ◽  
Development Of Resistance ◽  
Emerging Viral Diseases ◽  
Hiv 1

Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEAD-box polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.

scholarly journals In Vitro Selection of Highly Darunavir-Resistant and Replication-Competent HIV-1 Variants by Using a Mixture of Clinical HIV-1 Isolates Resistant to Multiple Conventional Protease Inhibitors

2010 ◽  
Vol 84 (22) ◽  
pp. 11961-11969 ◽  
Author(s):  
Yasuhiro Koh ◽  
Masayuki Amano ◽  
Tomomi Towata ◽  
Matthew Danish ◽  
Sofiya Leshchenko-Yashchuk ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
In Vitro Selection ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Genetic Barrier ◽  
Development Of Resistance ◽  
Multiple Drug Resistant ◽  
Moderately Resistant ◽  
Hiv 1

ABSTRACT We attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1MIX) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1MIX became highly resistant to DRV, with a 50% effective concentration (EC50) ∼333-fold greater than that against HIV-1NL4-3. HIV-1MIX at passage 51 (HIV-1MIXP51 ) replicated well in the presence of 5 μM DRV and contained 14 mutations. HIV-1MIXP51 was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1MIXP51 had a resemblance with HIV-1C of the HIV-1MIX population, and selection using HIV-1C was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1CP51 , likely contributed to conferring a replication advantage on HIV-1MIXP51 by reducing intravirion cyclophilin A content. HIV-1MIXP51 apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1MIX through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1MIXP51 should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents.

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