A new form of antiviral combination therapy predicted to prevent resistance from arising, and a model system to test it.
Combination therapy in the treatment of viral infections in which, for example, three different drugs against three different targets on three independent proteins are administered, has been highly successful clinically. However, it is only a matter of time before a virus will arise resistant to all three drugs, because the mutations leading to drug resistance are independent of each other. But, what if the mutations leading to drug resistance are not independent of each other, but confer some cost to the virus? If the cost is too great, than resistance may not arise. To impose such a cost in the clinical treatment of viral infections, we propose a new form of combination therapy. Here, three different drugs against three different targets on the same virus-coded protein are administered. If the physiological functions of the three different target sites are not independent of each other, then, a mutation at one site may alter the physiological functions at the other sites. We present a model system in which to test the efficacy of this new form of triple combination therapy. Human adenovirus has a virus-coded proteinase that is essential for the synthesis of infectious virus. It contains an active site and two cofactor binding sites; the functions of the active site are dependent upon the cofactors interacting with their binding sites. We describe how to obtain drugs against the three different sites.
Mangel
W F
WF
Biology Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. Mangel@BNL.gov
McGrath
W J
WJ
Brown
M T
MT
Baniecki
M L
ML
Barnard
D L
DL
Pang
Y P
YP
D000256:Adenoviridae / Q000201:enzymology; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000502:physiology; D004359:Drug Therapy, Combination; D006678:HIV / Q000187:drug effects / Q000201:enzymology; D015658:HIV Infections / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D006801:Humans; D008954:Models, Biological; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D004247:DNA; D003546:Cysteine Endopeptidases; C091827:adenain