Pritelivir

Last updated
Pritelivir
BAY 57-1293 structure.svg
Names
Systematic IUPAC name
N-Methyl-N-(4-methyl-5-sulfamoyl-1,3-thiazol-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide
Identifiers
3D model (JSmol)
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C18H18N4O3S2/c1-12-17(27(19,24)25)26-18(21-12)22(2)16(23)11-13-6-8-14(9-7-13)15-5-3-4-10-20-15/h3-10H,11H2,1-2H3,(H2,19,24,25)
    Key: IVZKZONQVYTCKC-UHFFFAOYSA-N
  • InChI=1/C18H18N4O3S2/c1-12-17(27(19,24)25)26-18(21-12)22(2)16(23)11-13-6-8-14(9-7-13)15-5-3-4-10-20-15/h3-10H,11H2,1-2H3,(H2,19,24,25)
    Key: IVZKZONQVYTCKC-UHFFFAOYAL
  • Cc1c(sc(n1)N(C)C(=O)Cc2ccc(cc2)c3ccccn3)S(=O)(=O)N
Properties
C18H18N4O3S2
Molar mass 402.49 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pritelivir (development codes AIC316 or BAY 57-1293) is a direct-acting antiviral drug in development for the treatment of herpes simplex virus infections (HSV). This is particularly important in immune compromised patients. It is currently in Phase III clinical development by the German biopharmaceutical company AiCuris Anti-infective Cures AG. US FDA granted fast track designation for pritelivir in 2017 and breakthrough therapy designation 2020.

Contents

Medical use

Pritelivir is currently being developed for the treatment of immunocompromised patients with mucocutaneous HSV lesions that are resistant to acyclovir.

HSV in immunocompromised patients

Although HSV infection is very common in the general population, it rarely causes serious disease and is effectively contained by the immune system. In those with a weakened immune system such as transplant recipients, people receiving chemo- or radiotherapy, or HIV patients, an active HSV infection can cause disease in 35-68% of patients and may become severe or even life-threatening. [1]

Standard of care treatments

HSV treatment revolves around the use of nucleoside analogues (NA) which act via the viral DNA polymerase, causing DNA chain termination and prevention of viral replication. First-line treatment is generally acyclovir or its prodrug valacyclovir. Resistance to acyclovir is more common in HSV patients with weakened or suppressed immune systems, affecting between 4 and 25% of cases. [2] [3] [4] [5] [6]

Resistance to standard treatments

If HSV drug resistance is mediated by mutation(s) of the viral UL23 gene, which encodes the viral thymidine kinase (TK), then the pyrophosphate analogue foscarnet may be effective as a rescue treatment, since it does not require activation by TK. The use of foscarnet is commonly accompanied by restrictive toxicity, particularly nephrotoxicity. [7] If the virus also acquires resistance to foscarnet, then there is currently no FDA approved treatment.

Clinical research

Completed phase II clinical trials in otherwise healthy patients with genital herpes

Ongoing phase II / phase III clinical trials with pritelivir

A phase II / III multinational, comparator-controlled, clinical trial in immunocompromised patients with acyclovir-resistant mucocutaneous lesions is listed on ClinicalTrials.gov [12] and EudraCT. [13]

Pharmacology

Mechanism of action

Pritelivir is a member of the helicase-primase inhibitors (HPI), a novel class of direct-acting antiviral drugs acting specifically against HSV-1 and HSV-2. [14] [15] As the name suggests, the drugs act through inhibition of the viral helicase primase complex, encoded by the UL5 (helicase), UL8 (scaffold protein) and UL52 (primase) genes, which is essential for HSV replication. [16] The helicase primase complex is encoded separately from the viral DNA polymerase (encoded by the UL30 gene). Because HPIs i) do not target the viral DNA polymerase and ii) do not require activation by the viral thymidine kinase enzyme (encoded by the UL23 gene), mutations causing resistance to NAs are not protective against HPIs. Similarly, resistance to HPIs does not confer resistance to NAs.

See also

Related Research Articles

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References

  1. ↑ Wilck, M.B.; Zuckerman, R.A.; A. S. T. Infectious Diseases Community of Practice (2013). "Herpes simplex virus in solid organ transplantation". Am J Transplant. 13 (Suppl 4): 121–7. doi: 10.1111/ajt.12105 . PMID   23465005. S2CID   44969727.
  2. ↑ Zuckerman, R.; Wald, A.; A. S. T. Infectious Diseases Community of Practice (2009). "Herpes simplex virus infections in solid organ transplant recipients". Am J Transplant. 9 (Suppl 4): S104-7. doi: 10.1111/j.1600-6143.2009.02900.x . PMID   20070669. S2CID   205846431.
  3. ↑ Frobert, E.; Burrel, S.; Ducastelle-Lepretre, S.; Billaud, G.; Ader, F.; Casalegno, J.S. (2014). "Resistance of herpes simplex viruses to acyclovir: an update from a ten-year survey in France". Antiviral Res. 111: 36–41. doi:10.1016/j.antiviral.2014.08.013. PMID   25218782.
  4. ↑ Patel, D.; Marchaim, D.; Marcus, G.; Gayathri, R.; Lephart, P.R.; Lazarovitch, T.; Zaidenstein, R.; Chandrasekar, P. (2014). "Predictors and outcomes of acyclovir-resistant herpes simplex virus infection among hematopoietic cell transplant recipients: case-case-control investigation". Clin Transplant. 28 (1): 1–5. doi:10.1111/ctr.12227. PMID   24033498. S2CID   37729458.
  5. ↑ Danve-Szatanek, C.; Aymard, M.; Thouvenot, D.; Morfin, F.; Agius, G.; Bertin, I. (2004). "Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up". J Clin Microbiol. 42 (1): 242–9. doi:10.1128/JCM.42.1.242-249.2004. PMC   321677 . PMID   14715760.
  6. ↑ Chakrabarti, R.; Pillay, D.; Ratcliffe, D.; Cane, P.A.; Collingham, K.E.; Milligan, D.W. (2000). "Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance". J Infect Dis. 181 (6): 2055–8. doi:10.1086/315524. PMID   10837192.
  7. ↑ SmPC
  8. ↑ NCT01047540
  9. ↑ Wald, A.; Timmler, B.; Magaret, A.; Warren, T.; Trying, S. (2014). "Helicase-primase inhibitor pritelivir for HSV-2 infection". N Engl J Med. 370 (3): 201–10. doi: 10.1056/NEJMoa1301150 . PMID   24428466.
  10. ↑ NCT01658826
  11. ↑ Wald, A.; Timmler, B.; Warren, T.; Trying, S.; Johnston, C. (2016). "Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences: A Randomized Clinical Trial". JAMA. 316 (23): 2495–2503. doi:10.1001/jama.2016.18189. hdl: 1805/14200 . PMID   27997653.
  12. ↑ NCT03073967
  13. ↑ 2020-004940-27
  14. ↑ Biswas, S.; Jennens, L.; Field, H.J. (2007). "Single amino acid substitutions in the HSV-1 helicase protein that confer resistance to the helicase-primase inhibitor BAY 57-1293 are associated with increased or decreased virus growth characteristics in tissue culture". Arch Virol. 152 (8): 1489–500. doi:10.1007/s00705-007-0964-7. PMID   17404685. S2CID   23688945.
  15. ↑ Field, H.J.; Biswas, S. (2011). "Antiviral drug resistance and helicase-primase inhibitors of herpes simplex virus". Drug Resist Updat. 14 (1): 45–51. doi:10.1016/j.drup.2010.11.002. PMID   21183396.
  16. ↑ Crute, J.J.; Tsurumi, T.; Zhu, L.A.; Weller, S.K.; Olivo, P.D.; Challberg, M.D. (1989). "Herpes simplex virus 1 helicase-primase: a complex of three herpes-encoded gene products". Proc. Natl. Acad. Sci. U.S.A. 86 (7): 2186–2189. Bibcode:1989PNAS...86.2186C. doi: 10.1073/pnas.86.7.2186 . PMC   286876 . PMID   2538835.
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