Antivirals against human polyomaviruses: Leaving no stone unturned

Abstract

Human polyomaviruses (HPyVs) encompass more than 10 species infecting 30%-90% of the human population without significant illness. Proven HPyV diseases with documented histopathology affect primarily immunocompromised hosts with manifestations in brain, skin and renourinary tract such as polyomavirus-associated nephropathy (PyVAN), polyomavirus-associated haemorrhagic cystitis (PyVHC), polyomavirus-associated urothelial cancer (PyVUC), progressive multifocal leukoencephalopathy (PML), Merkel cell carcinoma (MCC), Trichodysplasia spinulosa (TS) and pruritic hyperproliferative keratinopathy. Although virus-specific immune control is the eventual goal of therapy and lasting cure, antiviral treatments are urgently needed in order to reduce or prevent HPyV diseases and thereby bridging the time needed to establish virus-specific immunity. However, the small dsDNA genome of only 5 kb of the non-enveloped HPyVs only encodes 5-7 viral proteins. Thus, HPyV replication relies heavily on host cell factors, thereby limiting both, number and type of specific virus-encoded antiviral targets. Lack of cost-effective high-throughput screening systems and relevant small animal models complicates the preclinical development. Current clinical studies are limited by small case

The Oxindole GW-5074 Inhibits JC Polyomavirus Infection and Spread by Antagonizing the MAPK-ERK Signaling Pathway

“…PML has been traditionally associated with HIV-AIDS, hematological malignancies, or treatment with immunomodulatory drugs including Tysabri (Natalizumab) ( 1 – 3 ). Current treatment guidelines focus on removing the cause of the underlying immunosuppression, and in recent years, antiretroviral therapies and extended-interval dosing have effectively reduced the incidence and severity of PML in these primary populations ( 1 – 4 , 8 – 11 ). Despite these successful management strategies, immunological and epidemiological obstacles still exist.…”

Discovery of novel druggable pockets on polyomavirus VP1 through crystallographic fragment-based screening to develop capsid assembly inhibitors

“…This family includes about a dozen human pathogens which cause a latent infection in 30% to 90% of the world's population but pose a distinct threat to immunocompromised individuals. 1 Such patients can develop a range of PyV-associated diseases which affect the urinary tract, brain and skin, including cancers. In particular, more than 80% of the world population is serologically positive to BK polyomavirus.…”

“…As systematically reviewed very recently, 1 no effective drugs are available to date against any of the polyomaviruses, despite multiple compounds being evaluated in preclinical and clinical studies. While cidofovir (a general nucleoside analogue active against a broad range of DNA viruses) has shown activity against BKPyV infection, this drug causes severe nephrotoxicity and induces renal failure in approximately 30% of patients.…”

“…5 BKPyV infection has also been associated with increased cancer risk, which is due to the ability of its large tumour antigen to bind and inhibit tumour suppressor proteins like p53 and retinoblastoma protein. 6 As systematically reviewed very recently, 1 no effective drugs are available to date against any of the polyomaviruses, despite multiple compounds being evaluated in preclinical and clinical studies. While cidofovir (a general nucleoside analogue active against a broad range of DNA viruses) has shown activity against BKPyV infection, this drug causes severe nephrotoxicity and induces renal failure in approximately 30% of patients.…”

Human genes with relative synonymous codon usage analogous to that of polyomaviruses are involved in the mechanism of polyomavirus nephropathy

“…Human polyomaviruses (HPyVs) are a group of 13 viruses characterized by a circular double-stranded DNA infecting a significant margin (30%-90%) of the human population worldwide ( Dalianis and Hirsch, 2013 ; Wu et al., 2021 ). HPyVs are endowed with a characteristic genetic material allowing them to produce viral proteins such as the large and small T antigens in the early region and the proteins of the capsid (VP1, 2, and 3) ( Moens et al., 2007 ; Burkert et al., 2014 ; Cook, 2016 ).…”