Mark Krystal
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View article: Exploring the impact of baseline and on‐treatment variables on durability of responses to fostemsavir through weeks 96 and 192 in the phase 3 <scp>BRIGHTE</scp> study
Exploring the impact of baseline and on‐treatment variables on durability of responses to fostemsavir through weeks 96 and 192 in the phase 3 <span>BRIGHTE</span> study Open
Objectives The gp120‐directed attachment inhibitor fostemsavir was effective in people with multidrug‐resistant (MDR) HIV‐1 in the BRIGHTE study. Understanding factors associated with virologic response can help clinicians optimize treatme…
View article: Antibody feedback establishes an affinity brake in the germinal center
Antibody feedback establishes an affinity brake in the germinal center Open
Summary Recent advances in mRNA vaccine technology have opened the door to novel types of antigen display, but little is yet known as to how B cells recognize and respond to these formats. By delivering an mRNA-LNP encoded membrane-bound i…
View article: Considerations for evaluating pragmatic design elements in digital health intervention trials: the case of Keep It Up! 3.0
Considerations for evaluating pragmatic design elements in digital health intervention trials: the case of Keep It Up! 3.0 Open
Application of both the PRECIS-2 and PRECIS-2-PS tools validated the pragmatic design of KIU! 3.0 as originally designed and after modifications during trial implementation. Our findings highlight instances where one tool may be more suita…
View article: Preclinical virology profiles of the HIV-1 capsid inhibitors VH4004280 and VH4011499
Preclinical virology profiles of the HIV-1 capsid inhibitors VH4004280 and VH4011499 Open
With its high degree of conservation and critical role in multiple steps of the HIV-1 life cycle, the HIV-1 capsid protein presents an attractive therapeutic target. Herein, the virologic properties of the HIV-1 capsid inhibitors VH4004280…
View article: Preclinical Profile of the HIV-1 Maturation Inhibitor VH3739937
Preclinical Profile of the HIV-1 Maturation Inhibitor VH3739937 Open
The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are describe…
View article: Exploring HIV-1 Maturation: A New Frontier in Antiviral Development
Exploring HIV-1 Maturation: A New Frontier in Antiviral Development Open
HIV-1 virion maturation is an essential step in the viral replication cycle to produce infectious virus particles. Gag and Gag-Pol polyproteins are assembled at the plasma membrane of the virus-producer cells and bud from it to the extrace…
View article: Characterization of clinical envelopes with lack of sensitivity to the HIV-1 inhibitors temsavir and ibalizumab
Characterization of clinical envelopes with lack of sensitivity to the HIV-1 inhibitors temsavir and ibalizumab Open
Previous data suggest a lack of cross-resistance between the gp120-directed attachment inhibitor temsavir (active moiety of fostemsavir) and the CD4-directed post-attachment inhibitor ibalizumab. Recently, analysis of HIV-1 envelopes with …
View article: The HIV-1 Capsid-Targeted Inhibitor GSK878 Alters Selection of Target Sites for HIV DNA Integration
The HIV-1 Capsid-Targeted Inhibitor GSK878 Alters Selection of Target Sites for HIV DNA Integration Open
Decades of effort have yielded highly effective antiviral agents to treat HIV, but viral strains have evolved resistance to each inhibitor type, focusing attention on the importance of developing new inhibitor classes. A particularly promi…
View article: Antiviral Properties of HIV-1 Capsid Inhibitor GSK878
Antiviral Properties of HIV-1 Capsid Inhibitor GSK878 Open
GSK878 is a newly described HIV-1 inhibitor that binds to the mature capsid (CA) hexamer in a pocket originally identified as the binding site of the well-studied CA inhibitor PF-74. Here, we show that GSK878 is highly potent, inhibiting a…
View article: CCDC 2209395: Experimental Crystal Structure Determination
CCDC 2209395: Experimental Crystal Structure Determination Open
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available …
View article: CCDC 2209396: Experimental Crystal Structure Determination
CCDC 2209396: Experimental Crystal Structure Determination Open
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available …
View article: A Phase 1 randomized study of GSK3732394, an investigational long-acting biologic treatment regimen for HIV-1 infection
A Phase 1 randomized study of GSK3732394, an investigational long-acting biologic treatment regimen for HIV-1 infection Open
Background The GSK3732394 multivalent protein was developed as a novel, long-acting, antiretroviral biologic treatment regimen with three independent, non–cross-resistant mechanisms for inhibiting HIV-1 entry. Methods A single-centre, Phas…
View article: Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors
Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors Open
View article: Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice
Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice Open
Eliciting broadly neutralizing antibodies (bnAbs) is the core of HIV vaccine design. bnAbs specific to the V2-apex region of the HIV envelope acquire breadth and potency with modest somatic hypermutation, making them attractive vaccination…
View article: CCDC 2176213: Experimental Crystal Structure Determination
CCDC 2176213: Experimental Crystal Structure Determination Open
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available …
View article: The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation Open
GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-95…
View article: Improving Drug Delivery While Tailoring Prodrug Activation to Modulate <i>C</i><sub>max</sub> and <i>C</i><sub>min</sub> by Optimization of (Carbonyl)oxyalkyl Linker-Based Prodrugs of Atazanavir
Improving Drug Delivery While Tailoring Prodrug Activation to Modulate <i>C</i><sub>max</sub> and <i>C</i><sub>min</sub> by Optimization of (Carbonyl)oxyalkyl Linker-Based Prodrugs of Atazanavir Open
Structure-property relationships associated with a series of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1 protease inhibitor atazanavir (1), designed to enhance the systemic drug delivery, were examined. Compar…
View article: Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric Integrase Inhibitor
Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric Integrase Inhibitor Open
Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because of their novel mechanism of action. Strategic modifications to the C5 moiety of a class of 4-(4,4-dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led…
View article: Week 96 Genotypic and Phenotypic Results of the Fostemsavir Phase 3 BRIGHTE Study in Heavily Treatment-Experienced Adults Living with Multidrug-Resistant HIV-1
Week 96 Genotypic and Phenotypic Results of the Fostemsavir Phase 3 BRIGHTE Study in Heavily Treatment-Experienced Adults Living with Multidrug-Resistant HIV-1 Open
In the phase 3 BRIGHTE study in heavily treatment-experienced adults with multidrug-resistant HIV-1, fostemsavir plus optimized background therapy (OBT) resulted in sustained rates of virologic suppression through 96 weeks. HIV-1 RNA <40 c…
View article: Design, Synthesis, and Preclinical Profiling of GSK3739936 (BMS-986180), an Allosteric Inhibitor of HIV-1 Integrase with Broad-Spectrum Activity toward 124/125 Polymorphs
Design, Synthesis, and Preclinical Profiling of GSK3739936 (BMS-986180), an Allosteric Inhibitor of HIV-1 Integrase with Broad-Spectrum Activity toward 124/125 Polymorphs Open
Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replica…
View article: Core Modifications to the 4-(4,4-Dimethylpiperidinyl) 2,6-Dimethylpyridinyl Class of Hiv-1 Allosteric Integrase Inhibitors
Core Modifications to the 4-(4,4-Dimethylpiperidinyl) 2,6-Dimethylpyridinyl Class of Hiv-1 Allosteric Integrase Inhibitors Open
View article: Utility of LC-MS Surrogate Peptide Methodology in the Development of a Combinectin, a Unique Anti-HIV Biologic Drug
Utility of LC-MS Surrogate Peptide Methodology in the Development of a Combinectin, a Unique Anti-HIV Biologic Drug Open
OBJECTIVES: The anti-HIV biologic drug combinectin is a construct of three independent HIV entry inhibitors and a pharmacokinetic (PK) enhancer, which together exhibit a synergistic increase of potency compared to the individual components…
View article: Prevalence of gp160 polymorphisms known to be related to decreased susceptibility to temsavir in different subtypes of HIV-1 in the Los Alamos National Laboratory HIV Sequence Database
Prevalence of gp160 polymorphisms known to be related to decreased susceptibility to temsavir in different subtypes of HIV-1 in the Los Alamos National Laboratory HIV Sequence Database Open
Background Fostemsavir, a prodrug of the gp120-directed attachment inhibitor temsavir, is indicated for use in heavily treatment-experienced individuals with MDR HIV-1. Reduced susceptibility to temsavir in the clinic maps to discrete chan…
View article: CCDC 2031147: Experimental Crystal Structure Determination
CCDC 2031147: Experimental Crystal Structure Determination Open
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available …
View article: Antiviral Activity, Pharmacokinetics, and Safety of BMS-488043, a Novel Oral Small-Molecule HIV-1 Attachment Inhibitor, in HIV-1-Infected Subjects
Antiviral Activity, Pharmacokinetics, and Safety of BMS-488043, a Novel Oral Small-Molecule HIV-1 Attachment Inhibitor, in HIV-1-Infected Subjects Open
BMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4 + lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 …
View article: Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense® Entry assay
Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense® Entry assay Open
Background Fostemsavir is a prodrug of a first-in-class HIV-1 attachment inhibitor, temsavir, that binds to gp120 and blocks attachment to the host-cell CD4 receptor, preventing entry and infection of the target cell. Previous studies usin…
View article: Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase
Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase Open
View article: Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors
Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors Open
View article: Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors
Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors Open
The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resist…
View article: Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors
Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors Open