Biology subjects

Nazarian, A.

Publications and source records attributed to Nazarian, A..

6 recordsLinked to original sources

bioRxiv2026

Orally Bioavailable SARS-CoV-2 Protease Inhibitors Bearing a Hydroxymethyl Ketone Warhead

The use of covalent warheads targeting the catalytic cysteine has been a cornerstone in coronavirus main protease (Mpro) inhibitor development, where various electrophilic motifs have been used including aldehydes, nitriles, ketoamides, and hydroxymethyl ketones (HMKs). Recent efforts have been mostly centered around nitrile warheads, given the success of compounds like Nirmatrelvir and Ensitrelvir in the clinic. However, finding and advancing alternative chemotypes with differentiating chemical and pharmacological profiles is essential for future pandemic preparedness. Among such alternatives, HMKs hold special interest because they balance reduced intrinsic electrophilicity with an excellent selectivity profile. Nevertheless, early HMK-based compounds, such as the clinical-stage Mpro inhibitor PF-00835231, suffered from poor oral bioavailability and therefore required intravenous administration, with or without prodrug derivatization of the hydroxyl group. Here, we describe our efforts in advancing the HMK field via the discovery of mCMX110, a lead that has superior potency, increased unbound exposure in vivo, and favorable oral bioavailability in preclinical studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/725542v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@40222aorg.highwire.dtl.DTLVardef@831b88org.highwire.dtl.DTLVardef@184a910org.highwire.dtl.DTLVardef@779095_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment ([~]40-106 mg) and one-month chemoprevention ([~]96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.

microbiology↗

bioRxiv2023

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof towards human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = PaxlovidTM), CMX990 has distinctly differentiated potency ([~]5x more potent in primary cells) and human in vitro clearance (>4x better microsomal clearance and >10x better hepatocyte clearance), with good in vitro-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

microbiology↗

bioRxiv2023

An In-Silico Testbed for Fast and Accurate MR Labeling of Orthopaedic Implants

AO_SCPLOWBSTRACTC_SCPLOWOne limitation on the ability to monitor health in older adults using Magnetic Resonance (MR) imaging is the presence of implants, where the prevalence of implantable devices (orthopedic, cardiac, neuromodulation) increases in the population, as does the pervasiveness of conditions requiring MRI studies for diagnosis (musculoskeletal diseases, infections, or cancer). The present study describes a novel multiphysics implant modeling testbed using the following approaches with two examples: - an in-silico human model based on the widely available Visible Human Project (VHP) cryo-section dataset; - a finite element method (FEM) modeling software workbench from Ansys (Electronics Desktop/Mechanical) to model MR radio frequency (RF) coils and the temperature rise modeling in heterogeneous media. The in-silico VHP Female model (250 parts with an additional 40 components specifically characterizing embedded implants and resultant surrounding tissues) corresponds to a 60-year-old female with a body mass index (BMI) of 36. The testbed includes the FEM-compatible in-silico human model, an implant embedding procedure, a generic parameterizable MRI RF birdcage two-port coil model, a workflow for computing heat sources on the implant surface and in adjacent tissues, and a thermal FEM solver directly linked to the MR coil simulator to determine implant heating based on an MR imaging study protocol. The primary target is MR labeling of large orthopaedic implants. The testbed has very recently been approved by the US Food and Drug Administration (FDA) as a medical device development tool (MDDT) for 1.5 T orthopaedic implant examinations.

biophysics↗

bioRxiv2018

Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex-disparities

BackgroundAlzheimers disease (AD) is the most common cause of dementia in the elderly and the sixth leading cause of death in the United States. AD is mainly considered a complex disorder with polygenic inheritance. Despite discovering many susceptibility loci, a major proportion of AD genetic variance remains to be explained.\n\nMethodsWe investigated the genetic architecture of AD in four publicly available independent datasets through genome-wide association, transcriptome-wide association, and gene-based analyses. To explore differences in the genetic basis of AD between males and females, analyses were performed on three samples in each dataset: males and females combined, only males, or only females.\n\nResultsOur genome-wide association analyses corroborated the associations of several previously detected AD loci and revealed novel significant associations of 54 single-nucleotide polymorphisms (SNPs) at a p-value of < 5E-06. In addition, 23 genes located outside the chromosome 19q13 region showed suggestive associations with AD at a false discovery rate of 0.05 in transcriptome-wide association and gene-based analyses. Most of the newly detected AD-associated SNPs and genes were sex specific, indicating sex disparities in the genetic basis of AD.\n\nConclusionsOur findings, particularly the newly discovered sex-specific genetic contributors, provide novel insight into the genetic architecture of AD and can advance our understanding of its pathogenesis.

neuroscience↗

bioRxiv2018

Methylation-wide association analysis reveals AIM2, DGUOK, GNAI3, and ST14 genes as potential contributors to the Alzheimer’s disease pathogenesis

Introduction: Alzheimers disease (AD) is a progressive complex neurodegenerative disorder with devastating impact on cognitive abilities. It is among the top 10 leading causes of death in the United States with no curative medications. Exploring genetic and non-genetic contributors to AD development is, therefore, of great importance.\n\nMethods: We investigated the AD-associated epigenetic changes by combing results from publicly available genome-wide association analyses and a large-scale methylation quantitative trait loci study.\n\nResults: Probes mapped to 133 genes were associated with AD with < 2.50E-06. Of these, four genes (i.e., GNAI3, AIM2, DGUOK and ST14) provided stronger evidence of possible role in AD pathogenesis as they were also significantly associated with AD in previous expression quantitative trait loci analyses and/or mouse model studies.\n\nDiscussion: Although the identified associations do not prove any definitive causal relationships with AD, they provide a list of prioritized genes for follow-up functional studies.

neuroscience↗