A5071450033- Enzyme Production and Characterization
- Biofuel production and bioconversion
- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Microbial Metabolic Engineering and Bioproduction
- Enzyme Structure and Function
- Catalysis for Biomass Conversion
- Microbial Metabolites in Food Biotechnology
- HIV/AIDS Research and Interventions
- Enzyme Catalysis and Immobilization
- Phytase and its Applications
- Viral gastroenteritis research and epidemiology
- Viral Infections and Immunology Research
- Polysaccharides and Plant Cell Walls
- Bee Products Chemical Analysis
- Biopolymer Synthesis and Applications
- Insect and Pesticide Research
- Virus-based gene therapy research
- Insect and Arachnid Ecology and Behavior
- Pineapple and bromelain studies
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Probiotics and Fermented Foods
University of Colorado Anschutz Medical Campus
2022-2025
Universidade de São Paulo
2020-2024
University of Colorado Denver
2023
Abstract Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short phenylalanine-glycine (FG) containing peptides with isolated capsid hexamers have been characterized, how these cellular factors functionally engage biologically relevant mature lattices is unknown. Here we show that prion-like low complexity regions (LCRs) enable avid binding to lattices. Structural studies revealed multivalent CPSF6 assembly mediated by LCR-LCR...
Lenacapavir (LEN) is a long-acting, highly potent HIV-1 capsid (CA) inhibitor. The evolution of viral variants under the genetic pressure LEN identified Q67H, N74D, and Q67H/N74D CA substitutions as main resistance associated mutations (RAMs). Here, we determined high-resolution structures hexamers containing these RAMs in absence presence LEN. Our findings reveal that Q67H change induces conformational switch, which adversely affects inhibitor binding. In unliganded protein, His67 side...
HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by enzyme integrase and blocked strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in clinic. Resistance to even best INSTIs a problem, mechanisms resistance are poorly understood. Here, we analyze combinations mutations E138K, G140A/S, Q148H/K/R, which confer INSTIs. The investigational drug 4d more effectively inhibited mutants compared with approved...
Lenacapavir (LEN) is a highly potent, long-acting antiretroviral medication for treating people infected with muti-drug-resistant HIV-1 phenotypes. The inhibitor targets multifaceted functions of the viral capsid protein (CA) during replication. Previous studies have mainly focused on elucidating LEN’s mode action ingress. Additionally, has been shown to interfere mature assembly egress. However, mechanism how LEN affects maturation unknown. Here, we show that pharmacologically relevant...
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization IN. Here, we present cocrystal structures IN with two potent ALLINIs, namely, BI-D and drug candidate Pirmitegravir. The reveal atomistic details ALLINI-induced interface between catalytic core carboxyl-terminal domains (CCD CTD). Projecting from their principal binding pocket on CCD dimer, compounds act as molecular glue...
Glycoside hydrolases (GHs) are essential for plant biomass deconstruction. GH11 family consist of endo-β-1,4-xylanases which hydrolyze xylan, the second most abundant cell wall biopolymer after cellulose, into small bioavailable oligomers. Structural requirements enzymatic mechanism xylan hydrolysis is well described members. However, over last years, it has been discovered that some enzymes from have a secondary binding sites (SBS), modulate activities, but mechanistic details molecular...
ABSTRACT Lenacapavir (LEN) is the first in class viral capsid protein (CA) targeting antiretroviral for treating multi-drug-resistant HIV-1 infection. Clinical trials and cell culture experiments have identified resistance associated mutations (RAMs) vicinity of hydrophobic CA pocket targeted by LEN. The M66I substitution conferred far highest level to inhibitor compared other RAMs. Here we investigated structural mechanistic bases how change affects LEN binding replication. high-resolution...
ABSTRACT Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based breakthrough assays identified the (Y99H/A128T IN) variant that confers substantial resistance to this inhibitor. Here, we...
ABSTRACT Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents that potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into phase 2a clinical trials. Previous cell culture-based breakthrough assays identified the (Y99H/A128T IN) variant confers substantial resistance to this inhibitor. Here, we have...
The heteropolysaccharide xylan is a valuable source of sustainable chemicals and materials from renewable biomass sources. A complete hydrolysis this major hemicellulose component requires diverse set enzymes including endo-β-1,4-xylanases, β-xylosidases, acetylxylan esterases, α-l-arabinofuranosidases, α-glucuronidases. Notably, the most studied xylanases glycoside hydrolase family 11 (GH11) have exclusively been endo-β-1,4- β-1,3-xylanases. However, recent analysis metatranscriptome...
Lenacapavir (LEN) is a highly potent, long-acting antiretroviral medication for treating people infected with muti-drug-resistant HIV-1 phenotypes. The inhibitor targets multifaceted functions of the viral capsid protein (CA) during replication. Previous studies have mainly focused on elucidating LEN's mode action ingress. Additionally, has been shown to interfere mature assembly egress. However, mechanism how LEN affects maturation unknown. Here, we show that pharmacologically relevant...