From nonpeptide toward noncarbon protease inhibitors: Metallacarboranes as specific and potent inhibitors of HIV protease

Abstract

HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a Ki value of 2.2 nM and a submicromolar EC50 in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 Å resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3 subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition. rational drug design ͉ aspartic proteases ͉ carboranes ͉ x-ray structure analysis ͉ virostatics

Inorganic Polyhedral Metallacarborane Inhibitors of HIV Protease: A New Approach to Overcoming Antiviral Resistance

“…6 Our main attention has been focused on cobaltacarboranes, specifically the [3-cobalt bis(1,2-dicarbollide)] -ion GB-18 (see Figure 1). There are several reports describing boron cluster-containing compounds as potential pharmaceuticals (antineoplastic and cytotoxic agents, estrogen agonists and antagonists, protein kinase C modulators), building blocks for BNCT (boron neutron capture therapy) pharmaceuticals, and agents for radioimaging.…”

Nonclassical Hydrophobic Effect in Micellization: Molecular Arrangement of Non‐Amphiphilic Structures

“…Cobalt bis(dicarbollides) and their derivatives are useful as, among others, enzyme inhibitors-HIV protease [18,19] or agents in radioactive ion extraction. [20] In the former case, closely apposed pairs of COSAN molecules accompanied by two Na + counterions bind in the HIV protease active site.…”

Ninety-Nine Is Not Enough: Molecular Characterization of Inhibitor-Resistant Human Immunodeficiency Virus Type 1 Protease Mutants with Insertions in the Flap Region

“…One of the major complications of such treatment is the evolution of drug-resistant PR variants (9). An understanding of the molecular mechanism of resistance is therefore critical for the design of novel, effective PIs that will maintain viral suppression (8,31,45).…”