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Rational design of peptide-based HIV proteinase inhibitors
N A Roberts1, J A Martin, D Kinchington
1Roche Products Ltd., Hertfordshire, United Kingdom.
Science (New York, N.Y.)
|April 20, 1990
Summary
New peptide derivatives effectively inhibit human immunodeficiency virus (HIV) proteinase, showing potent antiviral activity in nanomolar ranges with minimal toxicity. These novel HIV inhibitors offer a high therapeutic index for potential treatment.
Area of Science:
- Medicinal Chemistry
- Virology
- Biochemistry
Background:
- Human immunodeficiency virus (HIV) proteinase is a critical target for antiviral therapy.
- Developing effective and selective HIV proteinase inhibitors is essential to combat viral replication.
- The transition-state mimetic concept offers a rational design strategy for enzyme inhibitors.
Purpose of the Study:
- To design and synthesize novel peptide derivatives as potential inhibitors of HIV proteinase.
- To evaluate the inhibitory activity and selectivity of these compounds against HIV-1 and HIV-2 proteinases.
- To assess the antiviral efficacy and therapeutic index of the most potent inhibitors in cell-based assays.
Main Methods:
- Design of peptide derivatives based on the transition-state mimetic concept.
- Enzymatic assays to determine inhibition constants against purified HIV-1 and HIV-2 proteinases.
- Testing against structurally related human aspartic proteinases to assess selectivity.
- Cell-based assays using chronically infected CEM cells to evaluate inhibition of viral polyprotein cleavage (p55 to p24).
- Assessment of antiviral activity by measuring p24 antigen levels and syncytium formation.
- Cytotoxicity assays in various cell lines (C8166, JM) to determine therapeutic index.
Main Results:
- A series of peptide derivatives were successfully designed and synthesized.
- The most active compounds demonstrated potent inhibition of both HIV-1 and HIV-2 proteinases in the nanomolar range.
- These inhibitors exhibited high selectivity, with minimal activity against human aspartic proteinases at micromolar concentrations.
- Proteolytic cleavage of the HIV-1 gag polyprotein was inhibited in infected cells.
- Significant antiviral activity was observed in nanomolar concentrations across three different cell systems.
- No cytotoxicity was detected at relevant concentrations, indicating a high therapeutic index.
Conclusions:
- Novel peptide derivatives based on transition-state mimetics are potent inhibitors of HIV proteinase.
- These compounds exhibit significant antiviral activity and high selectivity, suggesting therapeutic potential.
- The developed HIV proteinase inhibitors represent a promising new class for the treatment of HIV infection.