VCU Center for Drug Discovery

Xiang-Yang Wang Lab

Our research has been focused on a better understanding stress sensing/responding molecules, innate pattern recognition receptors, and sentinel immune cells in orchestrating the host immune responses with a goal of developing innovative immune-modifying strategies to treat human diseases including cancer and autoimmune disorders. Our long-standing interest in translational cancer research led to a Phase I trial of melanoma-targeted recombinant chaperone vaccine with the potential to significantly impact patient outcomes. Building on these laboratory and clinical research efforts, we are engineering and testing the next-generation immunostimulatory agents (e.g., virus, antibodies) for potential translation to overcome the therapeutic barriers within the tumor microenvironment.

Yuesheng Zhang Lab

Research in Dr. Yuesheng Zhang’s lab at Massey Comprehensive Cancer Center and Department of Pharmacology and Toxicology is focused on discovery and development of novel therapeutic strategies that overcome drug resistance in cancer as well as identification of important cancer therapeutic targets. Dr. Zhang’s lab recently discovered a recombinant human protein known as PEPD-G278D that targets receptor tyrosine kinases EGFR and HER2. EGFR and HER2 are oncogenic drivers and major therapeutic targets in many types of human cancers. However, drug resistance to current anti-EGFR or anti-HER2 therapies is common. PEPD-G278D is a first-in-class dual degrader of EGFR and HER2. Preclinical studies in Dr. Zhang’s lab have shown that PEPD-G278D strongly inhibits the growth of cancer cells and tumors overexpressing EGFR, HER2 or their oncogenic mutants, and overcomes drug resistance. PEPD-G278D is a promising antitumor agent for cancers such as HER2- positive breast cancer and non-small cell lung cancer. Efforts are underway to advance PEPD-G278D to clinical evaluation.

Weinhui Hu Lab

Areas of Focus

• Cell-targeted gene therapy (AAV, lentivirus-like particles and nanoparticles)
• CRISPR/Cas genome editing
• mRNA-based antibody, vaccine and cytokine replacement therapy
• HIV/NeuroHIV cure
• Neurodevelopmental disorders and neurodegenerative diseases
• Gastrointestinal diseases

Research Projects

Target-specific delivery of CRISPR/Cas genome editors to cure infectious diseases such as HIV

T cell-targeting gene therapy

HIV/AIDS remains a major public health concern, affecting >39 million people worldwide. People with HIV even under long-term suppressive antiretroviral therapy (ART) develop various comorbidities such as precocious aging, neurocognitive disorders (HAND), cardiovascular diseases, and others. ART does not eliminate the integrated and silent HIV provirus in latently infected cells (mainly CD4 T cells). Cessation of ART leads to rapid viral rebound (within 2-3 weeks), even after many years of viral suppression. Novel approaches to permanently silence or completely eliminate HIV-1 latent proviruses are actively explored to achieve a “sterilizing” HIV cure. CRISPR/Cas genome editing strategy in preclinical animal studies and first-in-human Phase I/II clinical trial have shown a promise for HIV cure. Many viral and non-viral technologies have been developed for delivery of genome editors, which can be cDNA, mRNA, protein or ribonucleoprotein (RNP). Our approach involves CD4- targeted delivery of all-in-one Cas12f/multiplexed gRNAs for both in vitro and in vivo studies including HIV-infected humanized BLT-hIL34 mice, HIV transgenic Tg26 mice, EcoHIV-infected mice and SIV-infected rhesus macaques.

Microglia-targeted CRISPR/Cas editor for a cure of NeuroHIV

Although ART has greatly improved survival rates, around 50% people with HIV will still develop various degrees of HAND. Brain myeloid cells (BMC) including microglia (MG) and brain-associated macrophages have been extensively investigated for their contribution to NeuroHIV persistence, chronic neuroinflammation and HAND. Thus, eradication of HIV provirus in MG is a critical step towards cure of NeuroHIV. Since AAV gene therapy is most promising with thousands of ongoing clinical trials, significant efforts to minimize the CRISPR/Cas editors for fitting into AAV size limit have identified several miniature Cas editors such as Cas12f, Cas12j and Cas13x. A scientific gap in this field is lack of ideal AAV serotypes (AAV-BM) with high efficiency of both crossing the BBB (AAV-B) and targeting MG (AAV-M) in vivo. The current AAV-B serotypes have high efficiency to transduce neurons, astrocytes, and oligodendrocytes, but have limited ability of transducing MG. In contrast, several AAV-M serotypes have been identified for their efficient tropism to MG, but none of them can cross BBB efficiently. Therefore, three strategies are employed to fill in this critical gap:

1. Developing novel Exo-ERVLP technologies for endogenous scissor gene delivery to MG via AAV-B gene therapy
2. Screening AAV-BM serotypes in non-human primate (NHP) for SIV eradication
3. Screening AAV-BM serotypes in humanized MG mouse model and vascularized MG-containing cerebral organoids (vMCO) for HIV eradication

Exin21: A novel booster for mRNA stabilization and enhanced protein production in diverse applications

Proteins are vital in physiology and disease, serving the major targets for the biologics production. Despite progress, scalable protein production—especially in mammalian cells, which produce ~60–70% of biologics—remains challenging. Some proteins still show low yields, requiring better expression methods, particularly in vivo. We recently identified a novel 21-mer motif, Exin21, that boosts protein expression and secretion when inserted into coding regions. Its effect relies on the unique oligonucleotide sequence, not amino acid composition, as silent mutations abolish activity. Exin21 has been shown to boost PD1/CTLA4-targeted nanobody production in vitro and in vivo via LNP-mRNA delivery, improving antitumor efficacy. It also enhances vaccine efficacy for RSV and VZV. Various approaches are explored to validate Exin21 as a versatile booster, including in vitro scaling, in vivo functional testing, and boosting optimization using representative examples for antibodies, vaccines, and recombinant proteins (cytokines). Beyond improving yield and efficacy, Exin21 has the potential to reduce manufacturing costs, shorten production timelines, and enable more potent immune responses, particularly for mRNA-based vaccines and in vivo antibody or cytokine therapeutics.

Cancer continues to be challenging to public health, with nearly 2,000 deaths and 5,000 new cases per day. Center researchers focus on the discovery of new anti-cancer targets as personalized medicine and new approaches for the diagnosis, prevention, and treatment of cancer.  The following are some highlights.

• Potent inhibitors (IC₅₀ = 60 nM) have been developed to specifically target protein N-terminal methyltransferase 1, which represents a potential new approach to personalized cancer therapy including melanoma, colorectal and thyroid cancer ... Rong Huang
• G2.2 and its analogs structurally mimic heparin hexasaccharide; selectively inhibit cancer stem cells growth and self-renewal in colorectal, pancreatic and breast cells through activation of p38 MAPK involving IGF-1R and FGFR; G2.2 inhibits CSCs proliferation in mice xenografts ... Umesh Desai
• Irreversible inhibitors for the AGC kinase as an activity-based protein profiling to selectively identify and quantify the activated form in cells for detection and diagnosis ... Keith Ellis
• A small molecule called NT-7-16 has been identified as a microtubule destabilizer (30 nM potency) and anti-proliferation agent (10 nM potency) by binding in tubulin’s colchicine binding site; indications are that it overcomes taxol resistance. ISB3D researchers are leading the drug design efforts to discover even more efficacious agents ... Glen Kellogg
• The research in Dr. Jiong Li’s lab primarily aims to decipher the molecular mechanisms underlying dysregulated transcription that drive tumorigenesis and promote drug resistance of head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). We employ a combination of biochemical and biophysical methods, along with animal models, to investigate oncogenic transcription factors, including FOSL1, NF-kB, and β-catenin. Additionally, we are collaborating with structural biologists and medicinal chemists to develop innovative therapeutics, such as PROTAC degraders and small molecule inhibitors, selectively targeting transcriptional dysregulation in HNSCC and CRC.
• Dr. Huizhi Wang’s research focuses on understanding host immune responses to oral bacterial challenges and their role in periodontal disease progression. We investigate the molecular mechanisms that regulate the intensity and duration of oral bacteria-induced inflammation, with the long-term goal of identifying novel therapeutic targets to restore immune homeostasis. Currently, we are particularly interested in immunomodulators such as Serum and Glucocorticoid Kinase 1 (SGK1) and HDAC6. Another key area of research in Wang’s lab explores the role of oral bacteria in orodigestive cancer progression. Specifically, we investigate how pro-tumorigenic oral bacteria interact with the surrounding oral microbiota, shaping and being shaped by the immune microenvironment. This complex interplay potentiates cancer cell stemness and drives resistance to chemotherapy and/or immunotherapy. We are also committed to uncovering the molecular mechanisms that drive these processes, aiming to inform more effective therapeutic strategies.
• Dr. Brian Fuglestad's lab is using an advanced fragment-based drug discovery technique to design inhibitors for glutathione peroxidase 4. Inhibition of this protein induces ferroptosis in a variety of cancer cells, including certain types of drug resistant cancers.

Cognitive disorders become an increasingly important public health problem. Center researchers are working on new mechanism and therapeutic approaches to diseases like Alzheimer’s disease. The following are some highlights.

• Interactions of the Alzheimer’s amyloid peptide Aβ in its different forms with inflammatory proteins and the effects of these interactions on reactive oxygen release from activated rodent microglia ... H. Tonie Wright
• High-resolution X-ray crystallographic and cryo-electron microscopic structures of membrane proteins like the translocator protein for Alzheimer’s Disease drug discovery and development ... Youzhong Guo
• The main research interests in S. Zhang's laboratory are small molecule drug discovery and development for neurodegenerative diseases and inflammatory diseases using cutting edge technologies of medicinal chemistry. The currently ongoing research projects are:
  • To design and develop small molecules that target mitochondria complex I as neuroprotective agents for AD and other neurodegenerative diseases
  • To design and develop novel NLRP3 and GSDMD inhibitors as pharmacological tools and potential therapeutic agents for neurodegenerative disorders

• The Aerosol Research Group (Dr. Michael Hindle) focuses on the design and evaluation of novel aerosol drug delivery formulations targeting the lungs and nose. Their research explores the effects of physical, chemical, and formulation factors on aerosol performance, as well as the interaction with novel aerosol generation devices. Key projects include: Synthetic lung surfactant formulations for treating infants with respiratory distress syndrome (RDS) in low-resource environments. High-efficiency antibiotic and antiviral dry powder inhalers especially as potential inhaled medical countermeasures (MCM). Nasal aerosol delivery targeting nose to brain for treating a range of neurological disorders. The group collaborates with faculty in the College of Engineering who are experts in computational fluid dynamics and design engineering to develop innovative drug delivery systems.

Blood and cardiovascular diseases are the underlying cause of ~50% of all disease-related deaths in the US. Center researchers have developed several promising compounds as anticoagulants and antisickling agents. The following are some highlights.

• Four molecules (SPGG, SCI, SMI and SG-09) identified as preventing thrombosis at 25 – 250 g per mouse (1.25–12.5 mg/kg) dose as selective (>200-fold selectivity) factor XIa targeting anticoagulants through an allosteric inhibition mechanism ... Umesh Desai
• Allosteric modifiers of hemoglobin with nitric oxide releasing ability, which can increase both erythrocyte mobility and tissue oxygen and have potential application in stroke, myocardial infraction, and vasoconstriction prevention ... Martin Safo
• Structure-function studies of hemoglobin and rational design of antisickling agents to treat sickle cell disease; Two drugs have been developed, one currently in phase II clinical study, and the other preclinical study ...  Martin Safo
• Dr. Brian Fuglestad's lab is designing inhibitors targeting the NOX2 activation complex. Inhibition of NOX2 is known to reduce ischemia-reperfusion injury tissue damage. The approach of targeting the activation complex promises to avoid non-specificity problems associated with direct NOX2 inhibition.

The majority of chronic tobacco smokers develop emphematous lung, resulting in chronic obstructive pulmonary diseases (COPDs). No treatment is available to date that cures emphematous lung and all current treatments provide only symptomatic relief.

• Researchers at the center have developed novel molecules that not only prevent but cure emphysema/COPD ... Umesh Desai in collaboration with Masahiro Sakagami in the Dept. of Pharmaceutics, School of Pharmacy

• S. Zhang's laboratory is developing novel PET radiotracers by targeting NLRP3, GSDMD, and complex I as potential biomarkers to aid drug discovery and evaluations.

Infectious diseases pose a great threat to human health. Pathogens continually evolve to anti-infectious agents, making future generations more difficult to treat. This requires the continued development of new strategies to fight and prevent infection.   

• Development of a recombinant hepadnaviral core protein engineered to present malaria B cell and T cell epitopes in a highly immunogenic form that can function as a vaccine to elicit protective antibodies in recipients ... Darrell Peterson
• PHE as an anti-influenza agent that disrupts the M1 layer; it inhibits M1 oligomerization at 1-5 M and inhibits multiple viral strains including H1N1, H3N2, and H5N1 ... Umesh Desai and Martin Safo
• Many Gram-negative pathogenic bacteria, such as enteropathogenic E. coli, Salmonella enterica serotype Typhi and Yersinia pestis, use a conserved virulence apparatus called the Type III Secretion System (TTSS) to infect eukaryotic host cells. The synthesis of new and more potent TTSS inhibitors that function by preventing pathogenic bacteria from using their TTSS to cause infection is being pursued at the Center, as well as studies to more precisely define their molecular targets ... Aaron May
• Conjugation is a process used by many Gram-negative and Gram-positive bacteria to share antibiotic resistance genes, even if they have not been previously exposed to a specific drug.  This process is enabled by an apparatus called the Type IV Secretion System (T4SS), and inhibiting T4SS is a next-generation strategy to limit antibiotic resistance gene transfer ... Aaron May
• Structural studies of a S. aureus protease essential for ribosomal maturation and bacterial viability is being investigated as a basis for inhibitor design and screening ... Darrell Peterson, J. Neel Scarsdale, H. Tonie Wright in collaboration with Gail Christie in the Dept. of Microbiology, School of Medicine
• Human cytomegalovirus (CMV) is a significant human pathogen with a need for safer and more effective therapeutics. Center members are determining the crystal structure of the viral nuclease, which will form a basis for understanding the biochemical activities of the nuclease, its role in viral replication, and for exploiting the nuclease as a target for anti-viral drug discovery ... Martin Safo, Glen Kellogg in collaboration with Michael McVoy in the Dept. of Pediatrics, School of Medicine
• Dr. Chunhao Li‘s group studies bacterial genetics, physiology and host-pathogen interactions by using an approach of genetics, biochemistry, biophysics, cell biology, structural biology and animal models. His current research interest mainly focuses on three human pathogens: Borrelia burgdorferi, the causative agent of Lyme disease, Treponema denticola and Porphyromonas gingivalis, two keystone pathogens associated with periodontitis. His research has been found by NIAID and NIDCR since 2008
• Nitric oxide (NO) is a natural broad-spectrum antimicrobial. Dr. Xuewei Wang’s group designs innovative drug formulations that enable controlled nitric oxide release from medical implants, including catheters, cannulas and sensors. By releasing nitric oxide at the implant surface, these materials effectively inhibit the growth of both planktonic and biofilm bacteria, helping to prevent device-associated infections and related complications.
• The malaria parasites vary their surface proteins to avoid the host’s immune response, thereby perpetuating long-term infections. This so called “antigenic variation” is thought to be controlled by the NAD + -dependent histone deacetylase, PfSir2A, through epigenetic regulations. Therefore, pharmacological inhibition of PfSir2A may disrupt the mechanism of antigenic variation, and expose an extensive array of variants expressed on the surface of the parasites to stimulate broad, highly protective immunity. The study in Dr. Yana Cen’s lab has revealed new understandings on the regulation of PfSir2A activity, and new scaffolds for PfSir2A inhibitor. This is an exciting project that holds great potential for antimalarial drug discovery.

• Development of new and novel algorithms that are based on detecting and exploiting the underlying three-dimensional hydropathic interaction homologies within protein structure, which is a new strategy for protein structure prediction ... Glen Kellogg and J. Neel Scarsdale
• One of the evolving strategies for drug discovery is targeted inhibition of protein-protein interactions by small molecules. Unfortunately, the results to date have been unimpressive, and new approaches are necessary. Center researchers are exploring new theories and methods that exploit water, local pH and the hydrophobic effect ... Glen Kellogg, J. Neel Scarsdale in collaboration with Peter Uetz in the Center for the Study of Biological Complexity, Life Sciences
• Dr. Ka Un Lao’s research group focuses on integrating applied mathematics and machine learning with electronic structure theory to accelerate quantum chemistry calculations. These next-generation approaches significantly speed up quantum chemistry's core operations while maintaining chemical accuracy, enabling us to study larger and more complex systems. Specifically, our research is focused on three main directions: Integration of Grassmannians from differential geometry into quantum chemistry to enhance chemical discovery and improve the rational design of light-sensitive molecular devices; Integration of set theory-based fragmentation into quantum chemistry to enable accurate and efficient calculations of reaction and interaction energies in biological systems, offering valuable tools for studying enzymecatalyzed reactions and supporting new drug design efforts; Integration of machine learning data-driven models into quantum chemistry to address the scalability and transferability limitations of traditional machine learning models in predicting molecular properties.

The opioid crisis has been going on in this country for more than thirty years. Development of novel and more effective treatments to counteract opioid addiction and overdose is imperative.

• In Yan Zhang's lab, we have been working on the development of mu opioid receptor modulators to treat opioid addiction and fentanyl specific counteracting agents to treat fentanyl overdose.
• Studies in Dr. Dukat’s lab involve investigation of existing agents, and development of novel compounds, for the treatment of neuropsychiatric disorders, pain, and substance abuse. Methods routinely employed include synthesis, computational techniques (e.g., graphics modeling and docking at selected receptors and transporters; SAR and QSAR studies), and in vitro and in vivo pharmacological assays to investigate action and mechanisms of action. Of current interest are serotonergic psychedelic agents for use in treatment-resistant depression, and structurally novel types of agents (developed in our laboratory) that act as monoamine transporter (MAT) reuptake inhibitors, and others that act at OCTs (organic cation transporters).
• Dr. Pagare’s research focuses on developing novel mu-opioid receptor (MOR) modulators to counteract the effects of synthetic opioids, with the goal of creating safer treatments for opioid use disorder (OUD) and overdose. The emergence of ultra-potent MOR agonists, including fentanyl and nitazene derivatives, has increasingly challenged the efficacy of traditional OUD therapeutics. To address this, we integrate computational modeling, chemical synthesis, and in vitro and in vivo studies to design MOR-selective bitopic ligands that engage both orthosteric and allosteric sites. These ligands serve as pharmacological probes and tools to investigate receptor activation and inhibition, with the potential to inform novel therapeutics for OUD, safer analgesics, and harm reduction strategies.