Inhibition of Three Nucleotide Polymerases by Rifamycin Derivatives

Thompson, Frances M.; Tischler, Allan N.; Adams, Jesse W.; Calvin, Melvin

doi:10.1073/pnas.71.1.107

Cited by 15 publications

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“…RNA-dependent DNA polymerase activity partially purified from a transformed line of mouse embryo cells has been reported (24). Since only RSV-infected cells were used in the studies described in this report, the inhibition of RSV DNA polymerase activity by R-82 was tested and compared with other rifamycin derivatives (Table 1).…”

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Inhibition of infectious Rous sarcoma virus production by rifamycin derivative

Szabó¹,

Bissell²,

Calvin³

1976

J Virol

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A new rifamycin derivative, rifazone-82 (R-82), an inhibitor of viral RNA-dependent DNA polymerase, is selectively toxic to transformed chicken cells in culture. R-82 has now been shown to possess antiviral activity as well. The relatively nontoxic properties of R-82 to nontransformed cells have permitted the execution of experiments examining the effect of a rifamycin derivative on virus reproduction. Addition of low concentrations of R-82 (15 mug/ml) to cultures soon after Rous sarcoma virus infection prevents the spread of infection thoroughout the culture. This inhibition is not dependent on concomitant cellular transformation as identical results were obtained with cells infected with a transformation-defective Rous sarcoma virus. Addition of R-82 to cultures in which all the cells are infected does not substantially affect the yield of physical particles as measured by RNA-dependent DNA polymerase activity and by (3H) uridine incorporation into viral RNA. However, the infectivity of the progeny virus, as measured by focus-forming ability, is decrreased 95 to 99% by R-82 treatment.

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“…A number of new rifamycin derivatives synthesized in this laboratory have been shown to be inhibitors of murine leukemia virus RNAdependent DNA polymerase (24). One of these compounds, rifazone-82 (R-82), also selectively inhibits the growth of Rous sarcoma virus (RSV)-transformed chicken embryo cells in culture and prevents virus-induced focus formation (2).…”

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Inhibition of infectious Rous sarcoma virus production by rifamycin derivative

Szabó¹,

Bissell²,

Calvin³

1976

J Virol

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“…In addition, we have tested rifazone-82 (R-82), a new rifamycin which is to date the most selective inhibitor of viral RNAdirected DNA polymerase in vitro (6,21). We find that at low concentrations (3-10 gg,ml), R-82 can selectively inhibit the growth of transformed cells and prevent focus formation while allowing the normal cell growth and function to continue.…”

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“…The in vitro demonstration that RNAdirected 'DNA polymerase is inhibited by the action of some of these derivatives (6)(7)(8)(9)(10)(11)(12)(13) has raised the possibility that the drugs may inhibit focus formation by inhibiting the activity of RNA-directed DNA polymerase. Smith et al have shown recently that those rifamycin derivatives that are toxic to leukemic human leukocytes are also those that inhibit RNAdirected DNA polymerase best in vitro (14).…”

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Preferential Inhibition of the Growth of Virus-Transformed Cells in Culture by Rifazone-8 ₂ , a New Rifamycin Derivative

Bissell

Hatié

Tischler

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

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Rifampicin, a well-known derivative of rifamycin, has been shown to inhibit the replication of vaccinia virus in tissue culture when added at very high levels (>100 ug/ml) (15,16) and to reduce the incidence of adenovirus-induced tumors in male hamsters (16). In chick cells it has been argued that rifampicin (a) inhibits focus formation by Rous sarcoma virus (RSV) (1), (b) has no effect on transformation, as it is toxic to both normal and transformed cells (17), and (c) is preferentially toxic to transformed cells (20). Variation in culture conditions, serum concentration, and cell density undoubtedly play a role in such contradictory findings. For example, whether or not amphotericin B is present in culture medium may drastically change the result of focus inhibition (4, 19). Furthermore, the high concentration of rifampicin used in these experiments (20-80 ug/ml) under some conditions is quite toxic to normal cells and makes interpretation of these data very difficult. Rifampicin itself has little or no effect on activity of RNA-directed DNA polymerase in vitro at concentrations used in tissue culture studies (7,17,20). We have tested several new rifamycin derivatives synthesized in this laboratory that have been shown to be inhibitors of RNA-directed DNA polymerase in vitro and Abbreviations: R-82 or rifazone-82, rifaldehyde-N,N-di-n-octyl hydrazine-hydrazone; RSV, Rous sarcoma virus; B-RSV, Bryanhigh-titer strain of RSV; SR-RSV, Schmidt-Ruppin subgroup A strain of RSV; Rif, Rifampicin; DMB, 2',6'-dimethyl4'-benzyl-4'-desmethylrifampicin; (Me)2SO, dimethyl sulfoxide.inhibitors of focus formation in vivo in other cell systems (4-6).In addition, we have tested rifazone-82 (R-82), a new rifamycin which is to date the most selective inhibitor of viral RNAdirected DNA polymerase in vitro (6, 21). We find that at low concentrations (3-10 gg,ml), R-82 can selectively inhibit the growth of transformed cells and prevent focus formation while allowing the normal cell growth and function to continue. MATERIALS AND METHODSGrowth of Cell Cultures. Primary cultures were prepared from 10-day-old C/O or C/B type SPF chick embryos as described (23,24), except that amphotericin B (Fungizone) was eliminated at this point (25). The cells were seeded in medium 199, which was supplemented with tryptose phosphate broth (2%), calf serum (1%), and heated chicken serum (1%). The medium was changed on day 3. Secondary cultures were prepared 4 days after the primary seeding by trypsinization of primary cultures and were seeded at the desired cell concentration in 60-or 35-mm petri dishes. An additional 1 mg/ml of glucose was added to the medium at this time, bringing the final concentration of glucose to 11.00 mM, and calf-serum concentration was raised to 2%. For studies with transformed cultures, half the cells of a single embryo were infected 4 hr after primary seeding with 4 X 105 focusforming units of SR-RSV or B-RSV. Secondary cultures were prepared as above.Focus Assay. Assays were performed essentially as described (22), with sl...

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“…Two compounds are derivatives of rifamycin SV, well characterized as to their potent inhibition of reverse transcriptase and activity against Rauscher virus-induced splenomegaly (25,28): compound no. 120, 2,6-dimethyl benzyl 4-demethyl rifampin ( (Fig.…”

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Differential Susceptibility of Spleen Focus-Forming Virus and Murine Leukemia Viruses to Ansamycin Antibiotics

Horoszewicz

Leong

Carter

1977

Antimicrob Agents Chemother

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The streptovaricin complex (SvCx) and rifamycin SV derivatives display potent antiviral activity against the polycythemic strain of Friend leukemia virus (FV-P), as measured by a reduction in the number of spleen foci produced in mice. Such reductions may be explained by inactivation of functions of (i) the spleen focus-forming virus (SFFV), (ii) its “helper” murine leukemia virus (MuLV), or (iii) both viruses normally present in FV-P. We noted that preincubation of FV-P with fractionation products of SvCx, or derivatives of rifamycin SV, at low concentrations (3 to 5 μg/ml) reduces the number of spleen foci 80 to 97%, whereas titers of MuLV (from the same inoculum) remain unaffected (MuLV titers were measured by XC, S + L − , and “helper activity” assays). Our findings indicate a remarkable biological selectivity of ansamycins, as well as nonansamycin components of SvCx, against the transforming and defective spleen focus-forming virus as compared to MuLV. Thus, the drugs might be useful in distinguishing other types of oncornaviruses.

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Inhibition of Three Nucleotide Polymerases by Rifamycin Derivatives

Cited by 15 publications

References 13 publications

Inhibition of infectious Rous sarcoma virus production by rifamycin derivative

Inhibition of infectious Rous sarcoma virus production by rifamycin derivative

Preferential Inhibition of the Growth of Virus-Transformed Cells in Culture by Rifazone-8 ₂ , a New Rifamycin Derivative

Differential Susceptibility of Spleen Focus-Forming Virus and Murine Leukemia Viruses to Ansamycin Antibiotics

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Inhibition of Three Nucleotide Polymerases by Rifamycin Derivatives

Cited by 15 publications

References 13 publications

Inhibition of infectious Rous sarcoma virus production by rifamycin derivative

Inhibition of infectious Rous sarcoma virus production by rifamycin derivative

Preferential Inhibition of the Growth of Virus-Transformed Cells in Culture by Rifazone-8 2 , a New Rifamycin Derivative

Differential Susceptibility of Spleen Focus-Forming Virus and Murine Leukemia Viruses to Ansamycin Antibiotics

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Preferential Inhibition of the Growth of Virus-Transformed Cells in Culture by Rifazone-8 ₂ , a New Rifamycin Derivative