RESUMO
There is an urgent need for the development of novel antimicrobial agents that offer effective treatment against MRSA. Using a new class of dipeptide antibiotic TAN-1057A/B as lead, we designed, synthesized and evaluated analogs of TAN-1057A/B. Several novel dihydropyrimidinone antibiotics demonstrating comparable antibiotic efficacy while possessing favorable selectivity were identified.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
A novel compound, TTP-8307, was identified as a potent inhibitor of the replication of several rhino- and enteroviruses. TTP-8307 inhibits viral RNA synthesis in a dose-dependent manner, without affecting polyprotein synthesis and/or processing. Drug-resistant variants of coxsackievirus B3 were all shown to carry at least one amino acid mutation in the nonstructural protein 3A. In particular, three mutations located in a nonstructured region preceding the hydrophobic domain (V45A, I54F, and H57Y) appeared to contribute to the drug-resistant phenotype. This region has previously been identified as a hot sport for mutations that resulted in resistance to enviroxime, the sole 3A-targeting enterovirus inhibitor reported thus far. This was corroborated by the fact that TTP-8307 and enviroxime proved cross-resistant. It is hypothesized that TTP-8307 and enviroxime disrupt proper interactions of 3A(B) with other viral or cellular proteins that are required for efficient replication.
Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/genética , Enterovirus/efeitos dos fármacos , Mutação , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Chlorocebus aethiops , Enterovirus/genética , Enterovirus/metabolismo , Enterovirus/fisiologia , Enterovirus Humano B/efeitos dos fármacos , Enterovirus Humano B/genética , Enterovirus Humano B/metabolismo , Enterovirus Humano B/fisiologia , Células HeLa/virologia , Humanos , Testes de Sensibilidade Microbiana/métodos , Oximas , Poliovirus/efeitos dos fármacos , Poliovirus/genética , Rhinovirus/efeitos dos fármacos , Rhinovirus/genética , Rhinovirus/metabolismo , Rhinovirus/fisiologia , Sulfonamidas , Células Vero/virologia , Proteínas não Estruturais Virais/químicaRESUMO
By using a homology-based bioinformatics approach, a structural model of the vaccinia virus (VV) I7L proteinase was developed. A unique chemical library of approximately 51,000 compounds was computationally queried to identify potential active site inhibitors. The resulting biased subset of compounds was assayed for both toxicity and the ability to inhibit the growth of VV in tissue culture cells. A family of chemotypically related compounds was found which exhibits selective activity against orthopoxviruses, inhibiting VV with 50% inhibitory concentrations of 3 to 12 microM. These compounds exhibited no significant cytotoxicity in the four cell lines tested and did not inhibit the growth of other organisms such as Saccharomyces cerevisiae, Pseudomonas aeruginosa, adenovirus, or encephalomyocarditis virus. Phenotypic analyses of virus-infected cells were conducted in the presence of active compounds to verify that the correct biochemical step (I7L-mediated core protein processing) was being inhibited. Electron microscopy of compound-treated VV-infected cells indicated a block in morphogenesis. Compound-resistant viruses were generated and resistance was mapped to the I7L open reading frame. Transient expression with the mutant I7L gene rescued the ability of wild-type virus to replicate in the presence of compound, indicating that this is the only gene necessary for resistance. This novel class of inhibitors has potential for development as an efficient antiviral drug against pathogenic orthopoxviruses, including smallpox.