Integration of human immunodeficiency virus (HIV) into host DNA to form provirus is a critical step in HIV replication, and it is mediated by Integrase (IN) enzyme encoded by the virus. Compounds containing a, b diketo (b-DK) motif with carboxylate, triazole or tetrazole as the terminal functional group demonstrate potent IN inhibition with anti-viral activity. However, the b-DK motif containing compounds are not pharmacologically suitable. The reactive aand bketo moieties form covalent complexes with a-acidic glycoproteins in vivo and reduce the bioavailability as well as impair cellular uptake of the compounds. Since the pharmacological utility of the b-DK motif containing compounds is principally restricted to the reactive a, bketo groups, suitable alternate motif to the b-DK motif may provide pharmacologically useful candidates. In this context, aminocarboxylate motifs were investigated and oxalohydroxamic acid (OHA) motif was identified as surrogate of a, b-DK motif. Substitution of OHA motif in the aryl group of the b-DK inhibitor resulted in potent lead molecule against IN with anti-viral activity in nano molar range. The anti-viral mechanism of OHA motif containing compound is similar to that of the b-DK containing compounds. In the OHA motif, the oxamate functions as a, bDK isosters and the hydroxamate functions as the terminal functional group involved in IN inhibition. The oxamate containing compounds have reversible plasma protein binding characteristics and the studies indicate that the oxamate motif can be considered as bioisosteric equivalent of the b-DK motif. Several additional functional groups that can be substituted for hydroxamate in the oxamate motif are identified through structure based analysis on the mechanism of IN inhibitors. Some of these functional groups may be suitable for restricting the emergence of drug resistance.

Public Health Relevance

Integration of human immunodeficiency virus (HIV) into host DNA is a critical step in HIV replication, and it is mediated by Integrase (IN) enzyme of the virus. Drugs against IN will be useful in the treatment of HIV infection. This Phase II proposal describes several classes of novel IN inhibitors based on the systematic study of the IN inhibitor pharmacophore and its mechanism. The development of these new classes of IN inhibitors was demonstrated with one potent lead molecule that inhibit the IN and virus replication at nano molar concentration. The rationally designed compounds of this proposal would increase the repertoire of the IN inhibitors which is hitherto limited and some of these compounds may be useful in the treatment of drug resistance to IN inhibitors.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-AARR-E (16))
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Turk, Steven R
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Panvirex, LLC
United States
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