Biology subjects

Goodenow, M. M.

Publications and source records attributed to Goodenow, M. M..

3 recordsLinked to original sources

bioRxiv2020

Molecular docking-based screening for novel inhibitors of the human immunodeficiency virus type 1 protease that effectively reduce the viral replication in human cells

Therapeutic pressure by protease inhibitors (PIs) contributes to accumulation of mutations in the HIV type 1 (HIV-1) protease (PR) leading to development of drug resistance with subsequent therapy failure. Current PIs target the active site of PR in a competitive manner. Identification of molecules that exploit non-active site mechanisms of inhibition is essential to overcome resistance to current PIs. Potential non-active site HIV-1 protease (PR) inhibitors (PI) were identified by in silico screening of almost 140,000 molecules targeting the hinge region of PR. Inhibitory activity of best docking compounds was tested in an in vitro PR inhibition biochemical assay. Five compounds inhibited PR from multiple HIV-1 subtypes in vitro and reduced replicative capacity by PI-sensitive or multi-PI resistant HIV-1 variants in human cells ex vivo. Antiviral activity was boosted when combined with Ritonavir, potentially diminishing development of drug resistance, while providing effective treatment for drug resistant HIV-1 variants.

molecular biology↗

bioRxiv2020

Role of the Matrix-Capsid Cleavage Site Polymorphism S124V of HIV-1 Sub-subtype A2 in Gag Polyprotein Processing

Subtype C and A HIV-1 strains dominate the epidemic in Africa and Asia, while sub-subtype A2 is found at low frequency only in West Africa. To relate Gag processing in vitro with viral fitness, viral protease (PR) enzymatic activity and in vitro Gag processing were evaluated. The rate of sub-subtype A2 Gag polyprotein processing, as production of the p24 protein, was reduced compared to subtype B or C independent of PR subtype, indicating that subtype A2 Gag qualitatively differed from other subtypes. Introduction of subtype B matrix-capsid cleavage site in sub-subtype A2 Gag only partially restored the processing rate. Unique amino acid polymorphism V124S at the matrix-capsid cleavage site, together with other polymorphisms at non-cleavage sites, are differentially influencing the processing of Gag polyproteins. This genetic polymorphisms landscape defining HIV-1 sub-subtypes, subtypes and recombinant forms are determinants of viral fitness and frequency in the HIV-1 infected population. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/382879v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@eb2312org.highwire.dtl.DTLVardef@14ba88eorg.highwire.dtl.DTLVardef@2715c3org.highwire.dtl.DTLVardef@5ba6a_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe polymorphism at matrix-capsid cleavage site, together with non-cleavage sites polymorphisms, direct the processing rate of the substrate, not the intrinsic activity of the enzyme. C_LIO_LIThe less prevalent and less infectious sub-subtype A2 harbors the matrix-capsid cleavage site polymorphism that we report as a limiting factor for gag processing. C_LIO_LISub-subtype A2 Gag polyprotein processing rate is independent of the PR subtype. C_LI

microbiology↗

bioRxiv2020

Unique Genotypic Features of HIV-1 C Gp41 Membrane Proximal External Region Variants during Pregnancy Relate to Mother-to-child Transmission via Breastfeeding

Mother-to-child transmission (MTCT) through breastfeeding remains a major source of pediatric HIV-1 infection worldwide. To characterize plasma HIV-1 subtype C populations from infected mothers during pregnancy that related to subsequent breast milk transmission, an exploratory study was designed to apply next generation sequencing and a custom bioinformatics pipeline for HIV-1 gp41 extending from heptad repeat region 2 (HR2) through the membrane proximal external region (MPER) and the membrane spanning domain (MSD). Viral populations during pregnancy from women who transmitted by breastfeeding, compared to those who did not, displayed greater biodiversity, more frequent amino acid polymorphisms, lower hydropathy index and greater positive charge. Viral characteristics were restricted to MPER, failed to extend into flanking HR2 or MSD regions, and were unrelated to predicted neutralization resistance. Findings provide novel parameters to evaluate an association between maternal MPER variants present during gestation and lactogenesis with subsequent transmission outcomes by breastfeeding. IMPORTANCEHIV-1 transmission through breastfeeding accounts for 39% of MTCT and continues as a major route of pediatric infection in developing countries where access to interventions for interrupting transmission is limited. Identifying women who are likely to transmit during breastfeeding would focus therapies during the breastfeeding period to reduce MTCT. Findings from our pilot study identify novel characteristics of gestational viral MPER quasispecies related to transmission outcomes and raise the possibility for predicting MTCT by breastfeeding based on identifying mothers with high-risk viral populations.

microbiology↗