Effect of Copper Acyclovir Complexes on Herpes Simplex Virus Type 1and Type 2 (HSV‐1, HSV‐2) Infection in Cultured Cells

Abstract

We have found that when copper, zinc or cobalt is bound to a suitable ligand, the appropriate complex exhibited a significant anti-HSV effect (Varadinova et al., 1993; 1996). Recently published data by Sagripanti et al. (1997) also show that the inhibition of HSV by copper was enhanced by reducing agents and that mechanism of the inactivation is similar as for copper-mediated DNA damage (Aruoma, et al. 1991; Dizdaroglu, et al., 1991; Toyokuni and Sagripanti, 1994). Therefore it was interesting to study the efect of Cu(ll) coordination compounds with acyclovir (ACV) on the replication of HSV in cultured cells. The experiments on cytotoxicity as well as on the activity of three different Cu-ACV complexes [Cu(ACV)2Cl2(H2O)2] = (A); [Cu(ACV)2(H2O)3](NO3)2.H2O = (B) and [Cu(ACV)2(H2O)2](NO3)2] = (C) towards virus replication, with special attention on the growth of ACV-resistant strain R-100 were performed on MDBK cells. ACV was used as a reference compound. The following results were obtained: 1) Increased cell’s viability in the presence of 20-40(g/ml ACV and decreased one in the presence of Cu-ACV complexes with relative level (A) >> (B) > (C); 2) Cu-ACV complexes are more cytotoxic than the ligand - ACV and the relative level is (C)>(B)>(A); 3) The anti-HSV effect of ACV can be modulated by copper at levels depending on the specificity of the particular virus strain: (i) for the ACV sensitive strain DA (HSV-1) - ACV ((A) > (C) > (B); (ii) for the ACV sensitive strain Bja (HSV-2) (A) > ACV > (C) > (B); (iii) for strain R-100 (ACVR, TKa) - (A) > ACV > (C) > (B). This findings are consistent with previously published data and undoubtedly show that Cu-ACV complexes could be useful in the treatment of HSV infections, especially when the causative agent is a resistant to ACV mutant.

ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma

“…Copper found in serum has been shown to inhibit wild-type HSV infection, and its topical use is currently being evaluated as an antiherpetic agent in patients with herpes skin lesions. 13–15 Consistent with these previous reports, a complete absence of GFP-positive cells was apparent when cells were infected in the presence of copper. However, the ATN-224 treatment completely reversed the copper-mediated inhibition of RAMBO replication ( Figure 4a ).…”

Ternary complexes metal [Co(II), Ni(II), Cu(II) and Zn(II)] – ortho-iodohippurate (I-hip) – acyclovir. X-ray characterization of isostructural [(Co, Ni or Zn)(I-hip)2(ACV)(H2O)3] with stacking as a recognition factor

“…Moreover, acyclovir is known as a powerful antiviral agent against Herpes simplex [18,19]. Several metal complexes with acyclovir are described in bibliography [20][21][22][23][24][25][26][27][28][29][30][31][32] and it is known that a 3d metal ion as Zn(II) [33] and Cu(II) [34] or Pt(II) [30] can modulate the activity of acyclovir. For example it was known that the binary complex between Zn(II) and acyclovir presents an interesting anti-Herpes simplex virus activity, increased up to five times as compared to that acyclovir applied alone [33] possibly due to synergistic effects between metal ion and ligand.…”

Copper Chelation Enhances Antitumor Efficacy and Systemic Delivery of Oncolytic HSV

“…Apart from increasing angiogenesis, copper (Copper) has been shown to inhibit wild-type HSV-1 replication in cultured cells in vitro (16). Thus, we tested if ATN-224’s ability to chelate copper directly increases oHSV propagation.…”