Abstract: TH-PO0984
First-in-Class VP1 Targeting Small Molecule Therapeutic Development to Address BK Polyomavirus Reactivation in Kidney Transplant Recipients
Session Information
- Transplantation: Basic - Immune Biology, Tissue Injury, and Emerging Technologies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 2001 Transplantation: Basic
Authors
- Mani, Nagraj, Orthogon Therapeutics LLC (affiliate of Pledge Therapeutics LLC), Canton, Massachusetts, United States
- Martins, Fernando H., Orthogon Therapeutics LLC (affiliate of Pledge Therapeutics LLC), Canton, Massachusetts, United States
- Ross, Stephen, Orthogon Therapeutics LLC (affiliate of Pledge Therapeutics LLC), Canton, Massachusetts, United States
- Kunnath, John Paul, Orthogon Therapeutics LLC (affiliate of Pledge Therapeutics LLC), Canton, Massachusetts, United States
- Deans, Erin E., Orthogon Therapeutics LLC (affiliate of Pledge Therapeutics LLC), Canton, Massachusetts, United States
- Úbeda Nicolau, Cristina, Pledge Tx B.V., Leuven, Belgium
- Bandara, Asanga, Pledge Therapeutics, LLC, Canton, Massachusetts, United States
- Hamilton, Nicholas B., Pledge Therapeutics, LLC, Canton, Massachusetts, United States
- De Graef, Steff, Pledge Tx B.V., Leuven, Belgium
- Akkermans, Onno, Pledge Tx B.V., Leuven, Belgium
- Vaneerdewegh, Sine, Pledge Tx B.V., Leuven, Belgium
- Selvaraj, Brinda, Orthogon Therapeutics LLC (affiliate of Pledge Therapeutics LLC), Canton, Massachusetts, United States
- Chitalia, Vipul C., Boston Medical Center, Boston, Massachusetts, United States
- Weeks, Stephen D., Pledge Tx B.V., Leuven, Belgium
- Munawar, Ali, Pledge Therapeutics, LLC, Canton, Massachusetts, United States
Background
BKPyV reactivation in transplant recipients can lead to complications such as viremia, nephropathy, and graft dysfunction. While no approved antivirals exist, VP1-targeting monoclonal antibodies show limited efficacy due to VP1 sequence variation in receptor-binding domains. VP1-targeting with small molecules offer advantages by maintaining activity across BKPyV variants and penetrating renal sanctuaries of viral replication—barriers where antibodies are ineffective.
Methods
X-ray crystallography, medicinal chemistry, and computational modeling guided compound optimization. Confocal and electron microscopy were used to evaluated compound effect on virus lifecycle and capsid architecture, respectively. Binding affinity, antiviral activity, cytotoxicity, and in vitro ADME/safety profiles confirmed transplant-compatible druglike properties.
Results
A rational drug discovery program identified small-molecule compounds engaging an essential, highly conserved intracellular VP1 domain distinct from the variable antibody-binding cleft engaged by antibodies. Inhibitors showed sub-nanomolar binding affinity and potent antiviral activity in human renal epithelial cells with exceptional selectivity indices exceeding >10,000-fold. Critically, antiviral efficacy was preserved across BKPyV genotypes and clinical isolates (pan-genotype activity) independent of BC-loop variation. Compounds altered capsid architecture and blocked viral replication. Favorable ADME profiles included CYP450 compatibility, no renal transporter engagement (OATs, OATPs, OCTs, PepTs), stability in liver/kidney microsomes, and favorable solubility in physiological fluids in alignment with use in kidney and hematopoietic transplant patients.
Conclusion
Small-molecule inhibitors targeting conserved intracellular VP1 regions circumvent the limitations of antibody approaches, enabling uniform tissue penetration and antiviral activity. The profile supports further preclinical development across the clinical continuum: pre-transplant prophylaxis, preemptive intervention for viruria or viremia, and treatment of established BKPyV disease including nephropathy and hemorrhagic cystitis, with application in D+/R-, ATG induction and retransplant populations. This work establishes a new therapeutic class with potential to preserve allograft function without compromising immunosuppression.