About

Edward Arnold is a Distinguished Professor in the Department of Chemistry and Chemical Biology at Rutgers University. His major research interests include Computational Biology, Drug Discovery, Structural Biology, and Virology. Dr. Arnold's laboratory, established at the Center for Advanced Biotechnology & Medicine in 1987, focuses on understanding molecular mechanisms of drug resistance and applying structure-based drug design for the treatment of serious human diseases. The lab employs research tools from diverse fields such as X-ray crystallography, molecular biology, virology, protein biochemistry, and macromolecular engineering. His team has extensively studied the structure and function of reverse transcriptase (RT), an essential component of the AIDS virus and a primary target of anti-AIDS drugs. Using X-ray crystallography, they have solved the three-dimensional structures of HIV-1 RT in various complex states, revealing detailed insights into polymerase structure-function relationships, mechanisms of drug inhibition and resistance, and aiding in the design of RT inhibitors. The research includes structural studies of HIV-1 RT with antiviral drugs, model segments of the HIV genome, and complexes with non-nucleoside inhibitors, contributing to the development of drugs such as Etravirine and Rilpivirine. Dr. Arnold's work involves collaborations with multiple research groups and access to synchrotron X-radiation sources. His laboratory has contributed to structure-based drug design efforts, including the discovery and development of non-nucleoside inhibitors with high potency against drug-resistant HIV-1 variants. These efforts have led to the approval of drugs like Etravirine and Rilpivirine by the FDA. The lab also explores structural studies of other molecular systems, including bacterial RNA polymerase holoenzyme complexes and influenza virus polymerase, aiming to gain broader insights into molecular processes of living systems.

Research topics

• Virology
• Computational biology
• Biology
• Biochemistry
• Chemistry
• Medicine
• Stereochemistry
• Biophysics
• Cell biology
• Genetics
• Combinatorial chemistry
• Organic chemistry

Selected publications

• Abstract 3851 Discovery of non-nucleoside inhibitors of the enterovirus D68 3D polymerase through crystallographic fragment- and high-throughput biochemical screening

  Journal of Biological Chemistry · 2026-05-01

  articleOpen accessSenior author
  PublisherDOI

• Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates

  Nature Communications · 2025-02-13 · 22 citations

  articleOpen access

  The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PLpro) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70Ub binding site in PLpro, we designed a series of quinoline analogs demonstrating potent PLpro inhibition and antiviral activity. Notably, the X-ray crystal structures of 6 lead compounds reveal that the 2-aryl substitution can occupy either the Val70Ub site as expected or the BL2 groove in a flipped orientation. The in vivo lead Jun13296 exhibits favorable pharmacokinetic properties and potent inhibition against SARS-CoV-2 variants and nirmatrelvir-resistant mutants. In a mouse model of SARS-CoV-2 infection, oral treatment with Jun13296 significantly improves survival, reduces body weight loss and lung viral titers, and prevents lung tissue damage. These results underscore the potential of quinoline PLpro inhibitors as promising oral SARS-CoV-2 antiviral candidates, instilling hope for the future of SARS-CoV-2 treatment. The SARS-CoV-2 papain-like protease inhibitor, Jun13296, displays potent oral antiviral efficacy in a mouse model of SARS-CoV-2 infection and inhibits SARS-CoV-2 variants and nirmatrelvir-resistant mutants, rendering it a promising antiviral candidate.

  PublisherOA PDFDOI

• Structure-guided design of SARS-CoV-2 PLpro inhibitors with <i>in vivo</i> antiviral efficacy

  Structural Dynamics · 2025-03-01

  articleOpen accessSenior author

  Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the culprit behind the COVID-19 pandemic, which has killed millions of people worldwide. SARS-CoV-2 harbors a crucial papain-like protease domain, named PLpro, in its non-structural protein 3 (nsp3). This enzyme is not only required for processing the viral polyprotein at the nsp1/2, nsp2/3, and nsp3/4 cleavage junctions but also impairs the host immune system by removing ubiquitin and ISG15 modifications from host proteins. Aiming to address the pressing need for additional oral antivirals due to emerging SARS-CoV-2 variants and drug-resistant mutants, we focused on targeting PLpro. Despite its relatively limited exploration compared to other viral proteins, its essential role in viral replication and impact on the host immune response warranted further investigation. In this study, we determined co-crystal structures of PLpro with nine inhibitors using X-ray crystallography and step-by-step modification of the compounds based on their interactions with their binding pocket. First, we discovered a novel binding site (the “Val70Ub site”) for the covalent inhibitor Jun11313 near the established BL2 groove pocket. Comparative analysis with ubiquitin-bound and ISG15-bound PLpro structures (PDB 6XAA and 7RBS) revealed that the thienyl group of Jun11313 occupied the same hydrophobic site as Val70 from ubiquitin and Leu152 from ISG15. Leveraging the Val70Ub site and the BL2 groove, we obtained multiple PLpro inhibitors with inhibitory constants (Ki values) in the two-digit nanomolar range. The co-crystal structures of SARS-CoV-2 PLpro with eight biarylphenyl PLpro inhibitors, Jun11941, Jun12129, Jun12303, Jun12162, Jun12199, Jun12197, Jun12145, and Jun12682, were solved (2.5–3.1 Å resolution). The lead compound, Jun12682, exhibited efficacy against SARS-CoV-2 and its variants (Ki = 38.5 to 63.5 nM), including nirmatrelvir-resistant strains, with EC50 values ranging from 0.44 to 2.02 μM. Twice-daily oral administration of Jun12682 significantly improved survival rates, reduced lung viral loads, and mitigated lesions in a mouse model of SARS-CoV-2 infection. These findings highlight the promise of PLpro inhibitors, particularly Jun12682, as potential oral antiviral candidates against SARS-CoV-2.

  PublisherDOI

• Crystallographic fragment screening of the dengue virus polymerase reveals multiple binding sites for the development of non-nucleoside antiflavivirals

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-05 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Dengue viruses (DENV) infect approximately 400 million people each year, and there are currently no effective therapeutics available. To explore potential starting points for antiviral drug development, we conducted a large-scale crystallographic fragment screen targeting the RNA-dependent RNA polymerase (RdRp) domain of the non-structural protein 5 (NS5) from DENV serotype 2. Our screening, which involved 1,108 fragments, identified 60 hit compounds across various known binding sites, including the active site, N pocket, and RNA tunnel. Additionally, we discovered a novel binding site and a fragment-binding hotspot in thumb site II. These structural findings open amenable avenues for developing non-nucleoside inhibitors and offer valuable insights for future structure-based drug design aimed at DENV and other flaviviral RdRps.

  PublisherOA PDFDOI

• Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals

  Journal of Medicinal Chemistry · 2025-09-02 · 1 citations

  articleOpen accessSenior authorCorresponding

  Dengue viruses (DENVs) infect approximately 400 million people each year, and currently, there are no effective therapeutics available. To explore potential starting points for antiviral drug development, we conducted a large-scale crystallographic fragment screen targeting the RNA-dependent RNA polymerase (RdRp) domain of the nonstructural protein 5 (NS5) from DENV serotype 2. Our screening, which involved 1108 fragments, identified 60 hit compounds across various known binding sites, including the active site, N pocket, and RNA tunnel. Additionally, we discovered a novel binding site and a fragment-binding hot spot in thumb site II. These structural findings open amenable avenues for developing non-nucleoside inhibitors and offer valuable insights for future structure-based drug design aimed at DENV and other flaviviral RdRps.

  PublisherOA PDFDOI

• Development of enhanced HIV-1 non-nucleoside reverse transcriptase inhibitors with improved resistance and pharmacokinetic profiles

  Science Advances · 2025-05-30 · 4 citations

  articleOpen accessCorresponding

  HIV-1 infection is a manageable chronic condition, with non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) remaining a cornerstone of antiretroviral therapy. Nevertheless, drug resistance to existing therapeutics is a serious and immediate concern. Using structure-based and scaffold-hopping approaches, we designed evolved diarylpyrimidine analogs targeting reverse transcriptase (RT), exploiting chemical space surrounding the NNRTI-binding pocket. We identified compounds 5i3 and 5e2 , with robust antiviral efficacy against wild-type HIV-1 and rilpivirine-resistant strains. Encouragingly, in vitro selection of mutant strains with 5i3 took 39 passages to select resistance, with no phenotypic cross-resistance observed with known RT drugs. Co-crystal structures of wild-type and mutant RT with 5i3 and 5e2 revealed their resilience toward resistance mutations due to enhanced conformational flexibility and positional adaptability. 5i3 exhibited good pharmacokinetic properties and favorable safety profiles, without substantial cytochrome P450 inhibition, and excellent oral bioavailability. These derivatives represent a promising scaffold for the development of anti-HIV drugs.

  PublisherDOI

• The antiviral BDGR-49 provides protection from lethal, neurotropic Venezuelan equine encephalitis virus intranasal infection in mice

  Journal of Virology · 2025-03-18 · 4 citations

  articleOpen access

  ABSTRACT Venezuelan, western, and eastern equine encephalitis virus (VEEV, WEEV, and EEEV) cause a febrile illness that may result in fatal neurological disease in humans and equines. Human infections are typically from mosquito bites, although cases from respiratory exposure in laboratory accidents have been documented. In addition to natural mosquito-borne infection, the potential biothreat inherent in the ability to disseminate these viruses via the respiratory route has driven the development of antiviral drugs for this route of exposure. To address this gap, we tested the prophylactic administration of a novel brain-penetrant, antiviral, BDGR-49, against a lethal intranasal challenge of VEEV, WEEV, or EEEV in BALB/c mouse model. BDGR-49 conferred 100% protection with 6 mg kg −1 twice per day for 6 days for VEEV, but not EEEV or WEEV. By 8 days post-infection (dpi), infectious virus, viral RNA, and viral antigen in the brain of BDGR-49-treated mice were significantly reduced. Brains of VEEV TrD-infected, BDGR-49-treated mice showed a significant reduction in the expression of genes associated with inflammation ( IFNB1 , TNF , IL6 , and CCL5 ) and cell death ( CASP4 , GSDMD , PYCARD , and ZBP1 ). At dpi 14, histopathology showed that neuronal lesions and inflammatory cell infiltrates were essentially absent, and viral antigen was not detected in the brains of VEEV TrD-infected, BDGR-49-treated mice. In summary, although BDGR-49 treatment showed significant promise for the treatment of mice exposed intranasally to VEEV, the more rapid and efficient entry of EEEV and WEEV by this route into the central nervous system will require additional optimization of the dosing regimen. IMPORTANCE Prophylactic and therapeutic treatment of viruses that cause encephalitis requires fast-acting drugs that rapidly penetrate the blood-brain barrier. Currently, clinicians have only a limited set of antivirals for the treatment of neurotropic infections such as herpesviruses or HIV-1, and none for alphaviruses, and treatment outcomes remain poor. New medical countermeasures will address the gap in treatment of viral encephalitis such as those caused by the neurotropic alphaviruses and others.

  PublisherDOI

• Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure

  Proceedings of the National Academy of Sciences · 2024-04-01 · 17 citations

  articleOpen access

  Drug resistance in HIV type 1 (HIV-1) is a pervasive problem that affects the lives of millions of people worldwide. Although records of drug-resistant mutations (DRMs) have been extensively tabulated within public repositories, our understanding of the evolutionary kinetics of DRMs and how they evolve together remains limited. Epistasis, the interaction between a DRM and other residues in HIV-1 protein sequences, is key to the temporal evolution of drug resistance. We use a Potts sequence-covariation statistical-energy model of HIV-1 protein fitness under drug selection pressure, which captures epistatic interactions between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the acquisition of DRMs as they arise in an ensemble of drug-naive patient protein sequences. We follow the time course of 52 DRMs in the enzymes protease, RT, and integrase, the primary targets of antiretroviral therapy. The rates at which DRMs emerge are highly correlated with their observed acquisition rates reported in the literature when drug pressure is applied. This result highlights the central role of epistasis in determining the kinetics governing DRM emergence. Whereas rapidly acquired DRMs begin to accumulate as soon as drug pressure is applied, slowly acquired DRMs are contingent on accessory mutations that appear only after prolonged drug pressure. We provide a foundation for using computational methods to determine the temporal evolution of drug resistance using Potts statistical potentials, which can be used to gain mechanistic insights into drug resistance pathways in HIV-1 and other infectious agents.

  PublisherOA PDFDOI

• Crystal structures of an HIV-1 reverse transcriptase second strand initiation complex with and without non-nucleoside inhibitors may explain slow nucleotide incorporation and high sensitivity to inhibition

  Biophysical Journal · 2024-02-01

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Expanding our knowledge of the SARS-CoV-2 polyproteins: Structural and biochemical insights into the viral processing

  Biophysical Journal · 2024-02-01 · 2 citations

  articleSenior author
  PublisherDOI

Recent grants

• NIH Grant P50GM103368

  NIH · $39.8M · 2017

• HIV-1 reverse transcriptase structure: function, inhibition, and resistance

  NIH · $15.0M · 1988–2019

• NIH Grant U19AI073975

  NIH · $5.4M · 2012

• NIH Grant P01GM066671

  NIH · $5.0M · 2008

• NIH Grant U54GM103368

  NIH · $22.0M · 2022

Frequent coauthors

• Bryn Seiriol

  University of Chicago

  447 shared

• N Wales

  University of Sydney

  422 shared

• William T. Peterson

  National Oceanic and Atmospheric Administration

  418 shared

• F. R. Hall

  Insigneo

  406 shared

• Martin Gardner

  368 shared

• St John'

  Bridge University

  364 shared

• Kalyan Das

  Rega Institute for Medical Research

  247 shared

• Stephen H. Hughes

  223 shared