The Body Covers: The XIII International AIDS Conference
New Antiretrovirals - I
July 12, 2000
We heard about drugs against "old targets":
DPC 681 and DPC 684: selective inhibitors of the viral protease active against resistant variants of HIV (WeOrA532)
New Protease InhibitorsThere is a need for second-generation protease inhibitors that are:
DuPont presented two potential candidates to fill this hole: DPC 681 and DPC 684. Both are potent inhibitors of the HIV-1 protease and active against virus with the D30N mutation, as well as several other mutational patterns of indinavir- and amprenavir-resistant strains. They are less protein bound than the currently available drugs. Initial pharmacokinetic data in animals suggest that doses that will provide therapeutic concentrations are feasible. Phase I studies will start soon. We will have to wait a few years until the drugs are available.
Comparative and combinatorial analysis of the HIV-1 entry inhibitors PRO 542, T-20 and PRO 140 (WeOrA533)
Synergy data was presented between PRO 542, a new fusion inhibitor and T-20. PRO 542 (CD4-IgG2) is a fusion protein in which a portion of an antibody molecule has been replaced with four copies of a fragment of human CD4, so the free HIV virus binds to this molecule and not the "real" CD4 in the cell. PRO 542 seems to interact with T-20 favorably, which in the future might permit the use of a lower dose of T-20 if used in combination. The need for high doses of T-20 is one of the most limiting factors of that drug.
PRO 140 is a monoclonal antibody to CCR5 that potently blocks HIV-1 entry but not CC-chemokine signaling through CCR5. This product does not interact with T-20.
Some very preliminary data was presented about other entry inhibitors like AOP-RANTES, TAK 779 and KRH-1120, all of them still seem far away of phase I trials.
Potent antiviral activity of second-generation NNRTIs DPC 961 and DPC 083 against group M and group O strains of HIV-1 (WeOrA536)
In this abstract, DuPont presented data on DPC 961 and DPC 083, two new NNRTIS with improved potency against NNRTI-resistant strains. Both drugs are quite potent in in vitro tests, and structurally related to efavirenz. They are active against most NNRTI resistant strains, even against the group O virus. Both have less protein binding in plasma that efavirenz and have extremely long half lives, especially DPC 083. It is unclear which one DuPont is going to develop. Previously they had selected DPC 961, but the development was stopped due to the frequency of CNS side effects. Both drugs look very promising.
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