Combination chemotherapy: interaction of 5-methoxymethyldeoxyuridine with adenine arabinoside, 5-ethyldeoxyuridine, 5-iododeoxyuridine, and phosphonoacetic acid against herpes simplex virus types 1 and 2

Abstract

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%.

Ribavirin antagonizes inhibitory effects of pyrimidine 2',3'-dideoxynucleosides but enhances inhibitory effects of purine 2',3'-dideoxynucleosides on replication of human immunodeficiency virus in vitro

“…Combinations of antiviral drugs are of interest not only for increasing their efficacy and reducing their toxicity, but also for diminishing the probability of drug-virus resistance development. Combinations of various antiviral drugs have been evaluated against various herpesviruses, i.e., herpes simplex virus (1,9), varicella-zoster virus (2), and cytomegalovirus (18). Recently, Hartshorn et al reported the synergistic inhibition of HIV-1 by recombinant interferon-aA and phosphonoformic acid (15) and also by recombinant interferon-aA and AzddThd (16).…”

Inhibitory effects of atropine, protamine, and their combination on hepatitis A virus replication in PLC/PRF/5 cells

“…When (2,6). Conversely, an additive interaction between two drugs may indicate that they share the same mode of action (5,27). If this commonly held interpretation is correct, then the antiviral effect observed with the protamine-atropine combination suggests that the two agents differ at least in certain aspects of their modes of antiviral action.…”

Structure and conformation of 5-methoxymethyl-1-(2′-deoxy-β-D-lyxofuranosyl)uracil

“…The weighted time-averaged nrnr couplings are related to the couplings of the individual conformers and their relative populations by eqs. [2] and [3] where x denotes the mole fraction of each conformer present.…”

“…Our laboratory has been interested in viral chemotherapy, and, more specifically, the effect of nucleoside analogs on herpes simplex virus infections (1)(2)(3)(4)(5)(6)(7)(8). The nucleoside, 5-methoxymethyl-2'-deoxyuridine (MMdUrd), was synthesized (9) and its selective activity against herpes simplex virus was discovered in the early seventies (2).…”