The antiviral activity of 5-methoxymethyl-2'-deoxyuridine (MMUdR) was compared with that of 5-iodo-2'-deoxyuridine (IUdR), 5-ethyl-2'-deoxyuridine (EtUdR), adenine arabinoside (Ara-A), and phosphonoacetic acid (PAA) against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). MMUdR was more potent than Ara-A and PAA but less active than EtUdR and IUdR against HSV-1 in rabbit kidney (RK-13) cells. In Vero cells, the antiviral activities of MMUdR, Ara-A, and PAA against HSV-1 were of the same order of magnitude. The antiviral potency against HSV-2 varied with the strain of virus used. All strains of HSV-2 were markedly inhibited by EtUdR and IUdR and to a lesser degree by PAA. However, considerable variation was noticed in the susceptibility of HSV-2 strains to Ara-A and MMUdR. Interaction of MMUdR with Ara-A, EtUdR, IUdR, and PAA was investigated by the method of response isobolograms. MMUdR showed synergistic activity in combination with Ara-A and PAA but antagonistic activity in combination with EtUdR and IUdR against herpesviruses. Minimum toxic dose (concentration required to produce definite evidence of microscopic cytotoxicity in rapidly growing RK-13 cells) was determined for each compound and was found to be 512, 172, 64, 8, and less than 0.5 microgram/ml for MMUdR, PAA, Ara-A, EtUdR, and IUdR, respectively. MMUdR was found to have the maximum antiviral index against HSV-1 (512) and HSV-2 strains X-265 (102) and ATCC (85). Antiviral index was defined as the minimum toxic dose divided by the dose that reduced plaque numbers by 50%.

The antiviral activity of several ether derivatives of 5-hydroxymethyldeoxyuridine against the herpesvirus of infectious bovine rhinotracheitis was determined in monolayer cultures of secondary bovine fetal kidney cells. 5-Methoxy-methyldeoxyuridine (OCH 3 UdR) was found to be markedly inhibitory against this virus. Pretreatment of the cells with OCH 3 UdR, simultaneous addition of OCH 3 UdR with virus to the cells, and postinfection treatment with OCH 3 UdR were found to be effective in inhibiting virus-induced cytopathogenic effect. Against this virus, OCH 3 UdR was found to be as potent as 5-iododeoxyuridine and cytosine arabinoside. The α-anomer of OCH 3 UdR did not show antiviral activity. Preliminarly toxicity studies indicate that OCH 3 UdR has a very low acute toxicity.

GVPTA, V. S., and MELDRUM, J. B. Purification and properties sf thymidylate synthetase frsm pig thymus.Can. J. Biochem. 9,352-362 (1972).Thymidylate synthetase of pig thymus has been separated into two principal forms (designated I and 11, based on their order of elution) by chromatography on CM-Sephadex. By the use of (NH,),SB, the synthetase activity was separated into two fractions, and these were further purified by gel filtration using Sephadex G-IBQ and chromatography on CM-Sephadex. The highest specific activity obtained for I and I1 was 10.4 and 14.3 p o l of thymidine-5'-phosphate per hour per milligram of protein at 25" and pH 7.3 which represents a purification of 1688and 2630-fold, respectively. EBectrophoretically, I and II appear to be 78-88% pure. The Michaelis constants of 7.4 x 10s" M, 1.7 x M, and 1.8 x los4 M for HI with respect to deoxyuridine-5'-phosphate, 5,1O-methlenetetrahydrofolate, and uridine-5'-phosphate, respectively, have been determined. A double pH optima in the r a n g sf 4.4-4.8 and 7.2-7.4 in 2-N-wsrpholinoethane suBfonic acid buffer was exhibited by both forms. F o m s I and II showed maximal catalytic activity only in the presence of sulfkydryl compounds (a mM) and also had the ability to methylate uridine-5'-phosphate, although at a dower rate (ca. 28% and 13"/,, respectively) compared with the rase s f methylation of deoxyuridine-5'phosphate. Both deoxyuridine-5'-phosphate and tetrahydrofolate (to a lesser extent) aEorded protection to I1 against heat inactivation. GUPTA, V. S., et MELDRUM, J. B. Purification and properties of thymidylate synthetase frsm pig thymus. Can. J. Biochem. 5% 352-362 (1972). La thymidylixte synthktase de thymus de porc est dparie en deux fomes principales (appelees I et I1 selon B'ordre de leur elution) par chromatographie sulr CM-Skphadex. L'emploi du QNH,),S04 pemet de stparer la synthktase en deux fractions que i90n a purifikes par filtration sur gel de Stphadex G-IBKB et par chromatographie sur CM-Sephadex. L'activitk spkcifique H a plus &levee obtenue avec I et II est de 10.4 et 16.3 pmol de thymidine-5'-phosphate gar heure par mg de protkine A 25" et i+ pH 7.3, ce qui reprtsente Bane purification de I)ordre de 1688 et 2636) fois resptivement. EBectrophoretiquernent, I et I1 seraient de 70 B 80 pour-cent pures. Les constantes de Michaelis de B a forme IH, mesurees avec le dksoxyuridine-5'-phosphate, B e 5,10-rnkthyl+netetrahydrofohte ct l'uridine-5'-phosphate, sont resptivement de 7.4 x M, 1.7 x BIB-5M et 1.8 x la-" M. Dans 1e tampon MES, les deux forms ont un double pH optimum: I'un entre 6.6 et 6.8 et l'autre entre 7.2 et 7.4. L'activitt catalytique de I et I1 est maximum seu%ernent en prksence de composes sulfbydryles (60 m M ) et toutes deux poss6dent le porevoir de mkthyier 1'uridine-5'-phosphate, mais a une vitesse plus lente (ca. 28% et 13% resydectivement) cornpark I celle de la methylation du desoxyuridine-5'phosphate. Le dboxyuridine-5'-phosphate et le tttrahydrofolate ( B un degrt moindre) protegent tous deux la forme HI mntae l'ina...

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The relative efficacy of 5-methoxymethyldeoxyuridine (MMUdR), adenine arabinoside (Ara-A), 5-iododeoxyuridine (IUdR) and the combination of MMUdR and Ara-A in the treatment of experimental herpes simplex keratitis was investigated in rabbits. Treatment was initiated either at 4 or 24 h post virus inoculation. The parameter used to evaluate effectiveness was lesion size. Each eye was graded daily for the first 5 days and on alternate days thereafter to day 11. At concentrations of 2 or 5% both MMUdR and Ara-A were found to have potent antikeratitis activity. At 5% concentration, Ara-A provided essentially the same protection against herpes keratitis as 0.1% IUdR, while MMUdR was slightly less effective. The simultaneous application of 2% MMUdR and 2% Ara-A in combination was more effective than 5% MMUdR alone and was as effective as 5% Ara-A or 0.1% IUdR in controlling the viral keratitis.