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Wild-type and drug-resistant mutated HIV-1 proteases are active as dimers. This work describes the inhibition of their dimerization by a new series of alkyl tripeptides that target the four-stranded antiparallel beta-sheet formed by the interdigitation of the N- and C-monomer ends of each monomer. Analytical ultracentrifugation was used to give experimental evidence of their mode of action that is disruption of the active homodimer with formation of inactive monomer-inhibitor complexes. The minimum length of the alkyl chain needed to inhibit dimerization was established. Sequence variations led to a most potent HIV-PR dimerization inhibitor: palmitoyl-Leu-Glu-Tyr (Kid = 0.3 nM). Insertion of d-amino acids at the first two positions of the peptide moiety increased the inhibitor resistance to proteolysis without abolishing the inhibitory effect. Molecular dynamics simulations of the inhibitor series complexed with wild-type and mutated HIV-PR monomers corroborated the kinetic data. They suggested that the lipopeptide peptide moiety replaces the middle strand in the highly conserved intermolecular four-stranded beta-sheet formed by the peptide termini of each monomer, and the alkyl chain is tightly grasped by the active site groove capped by the beta-hairpin flap in a "superclosed" conformation. These new inhibitors were equally active in vitro against both wild-type and drug-resistant multimutated proteases, and the model suggested that the mutations in the monomer did not interfere with the inhibitor.
This review article focuses on the anti-herpesvirus agents effective against herpes simplex virus, varicella-zoster virus and cytomegalovirus, which have either been licensed for clinical use (idoxuridine, trifluridine, brivudin, acyclovir, valaciclovir, valganciclovir, famciclovir and foscarnet) or are under clinical development (CMX001 [the hexadecyloxypropyl prodrug of cidofovir], the helicase-primase inhibitor BAY 57-1293 [now referred to as AIC316], FV-100 [the valine ester of Cf 1743] and the terminase inhibitor letermovir [AIC246]).
The poxvirus vaccinia virus (VV) served as the model virus for which the first antivirals, the thiosemicarbazones, were identified. This dates back to 1950; and, although there is at present no single antiviral drug specifically licensed for the chemotherapy or -prophylaxis of poxvirus infections, numerous candidate compounds have been described over the past 50 years. These compounds include interferon and inducers thereof (i.e., polyacrylic acid), 5-substituted 2'-deoxyuridines (i.e., idoxuridine), IMP dehydrogenase inhibitors, S-adenosylhomocysteine hydrolase inhibitors, acyclic nucleoside phosphonates (such as cidofovir) and alkoxyalkyl prodrugs thereof (such as CMX001), viral egress inhibitors (such as tecovirimat), and cellular kinase inhibitors (such as imatinib).
Studies on the interaction with cells of the double-stranded complex of polyriboinosinic acid and polyribocytidylic acid [poly(rI).poly(rC)] have shown that the polymer binds rapidly to the cell and that of this only a very small amount penetrates into the cell (Bausek & Merigan, 1969). It has been shown further that the interferon inducing capacity of synthetic polynucleotides is markedly enhanced upon pre-incubation of the polymers at 37° in tissue culture medium in the absence of polycations (De Clercq, Wells & Merigan, 1970; De Clercq & Merigan, 1971) and that the preheated polymers bind more rapidly to the cell and persist for a longer time at the outer cell membrane than do the unheated polymers (De Clercq et al. 1971). Although these studies do not indicate whether the interferon response is triggered by the bulk of cell-associated polymer that resides at the cell surface or by the minute amount that penetrates into the cell (Bausek & Merigan, 1969; De Clercq et al. 1971), they suggest that the cell surface may play an important role in the production of interferon by synthetic polynucleotides.
Bromovinyldeoxyuridine (BVDU) is a highly potent and selective antiherpetic agent which offers great potential for the treatment of severe herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections in cancer patients. BVDU inhibits the replication of HSV-1 and VZV at a concentration as low as 1-10 ng/ml; and the proliferation of tumor cells transformed with the HSV-1 thymidine kinase gene is even inhibited by BVDU concentrations lower than 1 ng/ml. Moreover, BVDU is inhibitory to Epstein-Barr virus replication in vitro at a concentration of 0.02 micrograms/ml. Due to the action of pyrimidine nucleoside phosphorylases, BVDU is rapidly degraded to the free pyrimidine base bromovinyluracil (BVU). In contrast to BVDU, which is cleared from the bloodstream within 2-3 hours, BVU persists in the plasma for at least 24 hours. During this period BVU can be converted again to BVDU upon administration of deoxythymidine, deoxyuridine or any other deoxyribonucleoside capable of transferring its deoxyribosyl moiety onto BVU. BVU owes its long persistence in the bloodstream to the fact that it does not act as substrate for dihydrothymine dehydrogenase, the enzyme that catalyzes the first step in the catabolic pathway of pyrimidines. On the contrary, BVU acts as an efficient inhibitor of this enzyme and thereby prevents the degradation of fluorouracil (FU), a well-known anticancer agent. As a consequence, BVDU via BVU enhances the antitumor activity of FU, as has been demonstrated in the murine P388 leukemia model. Thus, BVDU may be useful in anticancer chemotherapy from several viewpoints, e.g. for treatment of intercurrent herpesvirus infections, and, in combination with FU, for treatment of those malignant diseases that are amenable to FU therapy.
