Biology subjects

Velez, G.

Publications and source records attributed to Velez, G..

3 recordsLinked to original sources

bioRxiv2021

TMPRSS2 structure-phylogeny repositions Avoralstat for SARS-CoV-2 prophylaxis in mice

Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target.1-3 We hypothesized drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo.4,5 Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor,6 inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle,5 Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans.

microbiology↗

bioRxiv2019

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Neurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients with PDE6A mutations and arRP mice with Pde6[a] mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, [a]-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.\n\nOne Sentence SummaryThe study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina.

biochemistry↗

bioRxiv2018

In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth.

Compound heterozygotes occur when different mutations at the same locus on both maternal and paternal chromosomes produce a recessive trait. Here we present the tool VarCount for the quantification of mutations at the individual level. We used VarCount to characterize compound heterozygous coding variants in patients with epileptic encephalopathy and in the 1000 genomes participants. The Epi4k data contains variants identified by whole exome sequencing in patients with either Lennox-Gastaut Syndrome (LGS) or Infantile Spasms (IS), as well as their parents. We queried the Epi4k dataset (264 trios) and the phased 1000 genomes data (2504 participants) for recessive variants. To assess enrichment, transcript counts were compared between the Epi4k and 1000 genomes participants using minor allele frequency (MAF) cutoffs of 0.5% and 1.0%, and including all ancestries or only probands of European ancestry. In the Epi4k participants, we found enrichment for rare, compound heterozygous mutations in six genes, including three involved in neuronal growth and development - PRTG (p=0.00086, 1% MAF, combined ancestries), TNC (p=0.0221% MAF, combined ancestries), and MACF1 (p=0.0245, 0.5% MAF, EU ancestry). Due the total number of transcripts considered in these analyses, the enrichment detected was not significant after correction for multiple testing and higher powered or prospective studies are necessary to validate the candidacy of these genes. However, PRTG, TNC, and MACF1 are potential novel recessive epilepsy genes and our results highlight that compound heterozygous mutations should be considered in sporadic epilepsy.

neuroscience↗