Combinations on the basis of netropsin or bis-derivative with activity antiherpes virus effect

 

The invention relates to medicine, namely to the development of new combinations Antiherpes virus effect of actions. The proposed combination of netropsin and acyclovir or ganciclovir, or phosphonooxy acid, or vidarabine (Ara-a). Also proposed a combination of bis-derived netropsin (Fig.2) and phosphonooxy acid, or vidarabine (Ara-a). Combination provide a high level of antiviral activity against herpes virus. 2 N. p. F.-ly, 1 tab., 2 Il.

The invention relates to the field of medical Virology and the development and creation of new combinations, providing cost-effective inhibition of infection caused by the herpes virus simple type 1, based on the use of two classes of compounds possessing a fundamentally different mechanism of suppression of herpes infection is on the one hand, derived netropsin and, on the other hand, modified nucleosides or phosphonooxy acid.

Antiviral activity and mechanism of action of antitumor antibiotics netropsin and distamycin well known. They are bound in a narrow groove of the DNA in swasti transcription [1, 2]. They also inhibit the activity of DNA topoisomerases I and II [3, 4], reverse transcriptase and integrase of human immunodeficiency virus [5]. However, these antibiotics are not found application in clinical practice because of the high toxicity.

One of the ways of increasing the selectivity (selectivity) of binding of these compounds with DNA is the synthesis of the bis-derivative netropsin and distamycin, covalently linked together in different orientations. Since the 80-ies, the group E. DeClercq al. studied the activity of the bis-derivative netropsin, United aliphatic chain comprising from 0 to 10 methylene units in the orientation of the tail-to-tail [6] and derived netropsin containing additional pyrrole cycles [7]. It was found that this group of compounds and antitumor activity may selectively inhibit the reproduction of the virus vaccine (chemotherapeutic index (KTI), 500). Was discovered the low activity of these compounds against herpes virus simple type 2 (KTI 6 and below). In relation to herpes virus simple type 1 (HSV-1) activity was almost absent. In some cases the minimum cytotoxic concentration was reduced by 5-10 times on sravnyatsya and distamycin or their derivatives with modified nucleosides or analogs of pyrophosphate was not found.

We have synthesized a series of bis-derivative netropsin caught selective inhibitors of reproduction of HSV-1 [8]. Was tested for their ability to enhance antiherpetic activity of known drugs that could reduce the toxic effect due to the lower active concentrations.

The invention consists in creating two-component combinations on the basis of netropsin or bis-derivative with modified nucleosides or phosphonooxy acid, providing a significant increase antiherpetic action compared with each of the combined antiviral compounds taken separately, and leading to increased selectivity antiherpetic action.

When studying the antiherpetic activity of the compounds and their combinations in vitro culture of Vero cells infected by HSV-1 strain L2with a multiplicity of 0.1 PFU/CL (where the FIGHT plaque-forming unit), and incubated under liquid environment support containing drugs, or combination of known concentrations. After 48 hours of incubation, when the control virus was developed 95-100% cytopathic effect was determined concentration, 50% ingibiruet is inali compounds was evaluated by calculating the index of FIC (fractional inhibitory concentration) as a sum of relations EID50each of the combined compounds in combination to EID50connections when used separately. When the value of the FIC <0.5 effect of the combination was assessed as expressed synergenic, FIC <0,9 as synergenic, FIC = 1,0 as an additive, at FIC >1,0 indifferent or antagonistic.

Example 1. Study of the biological activity of the combination of netropsin with modified nucleosides and phosphonooxy acid on the model of HSV-1 in cell culture.

The combination of netropsin acyclovir, ganciclovir, Ara-a and phosphonooxy acid leads to increased anti-herpes effect. 50% inhibition virusinduced cytopathic effect is achieved by the combined application of netropsin (Fig.1) inefficient concentration of 2.5 ág/ml (1/2 EID50and acyclovir, ganciclovir, vidarabine(Ara-a) and phosphonooxy acid, also taken in neeffektivnykh concentrations, 5, 5, 2, and 4 times smaller than EID50of these compounds, alone. Relevant data are shown in the table. The effect can be estimated as synergenic (FIC <0.9 for combination netropsin acyclovir, ganciclovir and phosphonooxy acid) or additive (FIC = 1.0 for combination with vidarabine (Origami and phosphonooxy acid on the model of HSV-1 in cell culture.

With combined use of bis-netropsin 1 (Fig.2) and acyclovir 50% inhibit virusinduced cytopathic effect is possible when used in concentrations of 33 and 6 times smaller than EID50when alone. When using bis-netropsin 1 in combination with ganciclovir concentrations can reduce 16 and 5 times, respectively (expressed synergenic effect). With a combination of bis-netropsin-1 phosphonooxy acid marked synergenic effect. When using bis-netropsin 1 in combination with vidarabine (Ara-a) 50% inhibition virusinduced cytopathic effect is achieved by the combined use of these compounds in concentrations equal to 1/2 CD50(additive effect).

Example 3. Study of cytotoxic effect of netropsin, bis-netropsin 1 and their combinations in vitro.

The table presents the results of studying the toxic effects of netropsin and bis-netropsin 1, as well as their combinations in the culture of Vero cells using the method of staining cells Trifanova blue, based on the ability of dead cells to be colored by the dye. After 72-hour incubation of the cells in the presence of the studied compounds or their combinations cells podsterech dies no more than 50% of the cells compared with control, inquireys without drugs. As can be seen from the table, the proposed combination of low toxicity: when used in the concentration range for active suppression of herpes infection, the value of CD50is not achieved.

Thus the combination of netropsin, bis-netropsin with modified nucleosides or phosphonooxy acid provides inhibiting additive and synergene action on the model of HSV-1 in cell culture.

Based amplification antiherpetic effect of combinations of bis-netropsins and modified nucleosides is the mechanism of their action on the synthesis of viral DNA. Netropsin and bis-netropsin specifically associated in the narrow groove of DNA with clusters of several at-base pairs, thus inhibiting the binding of proteins involved in regulation of transcription or DNA replication. Modified nucleosides as analogs of natural nucleosides as triphosphates, are included in the synthesized chain of viral DNA, resulting in termination of DNA synthesis, inhibit the activity of DNA polymerase. Phosphonooxy acid competes with the exchange of pyrophosphate from deoxynucleotides by binding to DNA-polymer is s (bis-netropsin with modified nucleosides or phosphonooxy acid), providing a significant increase antiherpetic action compared with each of the combined antiviral substances taken separately.

Literature

1. Dervan P. B., Burli R. W. // Current Opinion in Chem. Biol., 1999, V. 3, P. 688-693.

2. Korka, M. L., Yoon D., Goodsell D, et al. // Proc. Nat. Acad. Sci. USA, 1985. V. 82. P. 1376-1380.

3. Beerman, T. A., J. M. Woynarowski, Sigmund R. D. et al. // Biochim. Biophys. Acta, 1991, 1090. P. 52-60.

4. Burkhardt G., Simon H., Storl To et al. // J. Biomol. Struct. Dyn., 1997. V. 15. P. 81-95.

5. Filipowsky M. E., M. L. Kopka, Brazil-Zison M. et al. // Biochemistry, 1996. V. 35. P. 15397-15410.

6. J. W. Lown, K. Krowicki, J. Balzarini et al. // J. Med. Chem., 1989. V. 32. P. 2368-2375.

7. Baraldi P. O., G. Balboni, M. G. Pavani et al. // J. Med.Chem., 2001. V. 44. P. 2536-2543.

8. Andronov C. L., Grokhovsky S. L., Stern A. N. etc. // DAN, 2001. So 380, No. 4. S. 1-4.

Claims

1. Combination with Antiherpes virus effect of activity, consisting of netropsin and acyclovir or ganciclovir, or phosphonooxy acid, or vidarabine (Ara-a).

2. Combination with Antiherpes virus effect of activity consisting of bis-derived netropsin

and phosphonooxy acid or vidarabine (Ara-a).



 

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