SBIR-STTR Award

The goal of this project is to define the mechanism of anti-HIV activity of the small molecule pyrimidinedione HIV inhibitor IQP-0410. IQP-0410 inhibits HIV replication by two distinct mechanisms, acting as a nonnucleoside reverse transcriptase inhibitor while also potently suppressing virus entry. Unlike other NNRTIs, IQP-0410 inhibits both HIV-1 and HIV-2. The ability of IQP-0410 to prevent HIV entry into target cells occurs through a unique mechanism and the compound has been found to be more potent against clinical strains of HIV than against laboratory-derived viruses. The proposed research will utilize in vitro assays for selection and genotypic and phenotypic characterization of viruses resistant to IQP-0410. The program will focus on resistance engendering mutations within the viral gag, pol and envelope genes. A series of chimeric viruses containing wild type HIV-1 and HIV-2 sequences and sequences from resistant viruses at early, mid, and late stages of the selection process will be engineered to examine the contribution of the individual domains to IQP-0410 resistance and fitness of the virus. Pseudotype viruses possessing envelope glycoproteins from wild type and IQP-0410-resistant HIV-1 and HIV-2 viruses will be evaluated for their ability to infect target cells in the presence and absence of IQP-0410 and to quantify the effects of env mutations on the antiviral activity of IQP-0410. Pseudotype viruses with site-specific mutations engineered into envelope gp120 and gp41 domains identified by resistance selection will be utilized to define the conformational epitope within the envelope structure targeted by IQP-0410 in entry inhibition. Additionally, experiments will be performed to further understand the role of mutations in the gag gene and evaluate potential effects of IQP-0410 on virus maturation from infected cells. The impact of resistance mutations on the activity of viral RT and protease will also be examined using biochemical analysis. PUBLIC HEALTH RELEVANCE The goal of this grant proposal is to define the mechanism of action of a small molecule inhibitor of human immunodeficiency virus (HIV). The HIV inhibitor (IQP-0410) is known to inhibit two essential stages of virus infection and replication (reverse transcription and virus entry), and thus has the potential for providing a combination therapy with administration of a single drug. The proposed research will define the molecular targets of the compound within the virus, the mechanism by which the compound inhibits virus replication, and mutations that occur in the virus that make it resistant to the compound and the effects of these mutations on virus replication and infectivity.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
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Although IQP-0410 possesses a favorable pharmacokinetic, safety pharmacology and toxicity profile, we believe that additional enhancement of biological activity is possible through additional development activities with lead molecules defined as the most active reverse transcriptase and virus entry inhibitors defined in our Phase I SBIR studies. Structure-activity relationship data obtained with the pyrimidinediones from our Phase I SBIR project indicates that a second generation pyrimidinedione may also be expected to meet and potentially exceed these necessary properties for a next generation NNRTI. A number of initial lead compounds with greater entry and RT inhibitory potential and stability have been identified for further development. Based on the results of our Phase I proposal as well as our experience with the development of our current clinical candidate pyrimidinedione IQP-0410, we intend to employ traditional medicinal chemistry to improve the solubility and stability of a new select pyrimidinedione, which will be defined according to parameters including antiviral activity, metabolism, and preformulation characteristics. Upon selection of our second generation pyrimidinedione inhibitor, we will employ formulation science to better deliver the potent, stable and more soluble pyrimidinedione to enhance bioavailability and pharmacokinetics. It is our expectation that this Phase II SBIR effort will yield a significant improvement in the therapeutic utility and potency of our next generation clinical candidate.

Public Health Relevance:
Although the currently approved NNRTIs (nevirapine, delavirdine, efavirenz and etravirine) are highly potent, significant improvements in therapeutic utility are still required. A new generation of NNRTIs must be developed which will allow once per day dosing, exhibit significantly reduced toxicity, be amenable to dosing in women of child bearing age, and possess a significantly higher genetic barrier to resistance selection. The primary goal of this proposal is to define and begin IND-directed development of a second generation pyrimidinedione clinical therapeutic candidate from among the highly active lead compounds defined during the course of our Phase I project. These selected lead pyrimidinediones have been prioritized based on their relative potential to inhibit both reverse transcription and virus entry and all are sub-nanomolar to low nanomolar concentration inhibitors of HIV-1. Detailed biological evaluation of these molecules will be combined with efforts to optimize the formulation and delivery of a new lead molecule, as well as the use of medicinal chemistry to improve the solubility, stability, and bioavailability of the selected compound. Comparative evaluation of compound metabolism and protein binding will also be utilized to help prioritize and define the next generation pryimidinedione clinical candidate possessing highly optimized pharmacokinetic properties and the highest possible potency against wild type, NNRTI-resistant and MDR viruses.

Thesaurus Terms:
6-Chloro-4-Cyclopropylethynyl-4-Trifluoromethyl-1,4-Dihydro-2h-3,1-Benzoxazin-2-One; 6h-Dipyrido(3,2-B[{..}]2',3'-E)(1,4)Diazepin-6-One, 11-Cyclopropyl-5,11-Dihydro-4-Methyl-; Aids Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Algorithms; Animal Model; Animal Models And Related Studies; Antiproteases; Antiretroviral Therapy, Highly Active; Antiviral Agents; Antiviral Drugs; Antivirals; Bioavailability; Biochemical; Biologic Availability; Biological; Biological Availability; Blood Plasma; Canine Species; Canis Familiaris; Cells; Characteristics; Chemistry, Pharmaceutical; Clinical; Clinical Trials; Clinical Trials, Unspecified; Common Rat Strains; Data; Delavirdine; Deoxynucleotide-Triphosphate[{..}]dna Deoxynucleotidyltransferase (Rna-Directed); Development; Dogs; Dose; Drug Formulations; Drug Kinetics; Drug Resistance, Multiple; Drug Resistant, Multiple; Drug Resistance; Drug Resistant Viral; Drugs; Ec 2.7.7.49; Efv; Endopeptidase Inhibitors; Evaluation; Exhibits; Female Of Child Bearing Age; Female Of Childbearing Age; Formulation; Formulations, Drug; Generations; Genetic; Genetic Alteration; Genetic Change; Genetic Defect; Goals; Haart; Hiv; Hiv-1; Hiv-2; Hiv-I; Hiv-Ii; Hiv1; Hiv2; Htlv-Iii; Htlv-Iv; Highly Active Antiretroviral Therapy; Hour; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type Iii; Human T-Cell Lymphotropic Virus Type Iii; Human T-Lymphotropic Virus Type Iii; Human T-Lymphotropic Virus Type Iv; Human Immunodeficiency Virus 1; Human Immunodeficiency Virus 2; Human, General; Immunodeficiency Virus Type 1, Human; Immunodeficiency Virus Type 2, Human; In Vitro; Intermediary Metabolism; Investigational New Drug Application; Lav-2; Lav-Htlv-Iii; Laboratories; Lead; Liver Microsomes; Lymphadenopathy-Associated Virus; Metbl; Mammals, Dogs; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Medication; Medicinal Chemistry; Metabolic Processes; Metabolism; Mice; Microscopic; Microsomes; Multi-Drug Resistance; Multidrug Resistance; Murine; Mus; Mutation; Nnrti; Nnrti-Resistance; Nevirapine; Oral; Pathologic; Patients; Pb Element; Peptidase Inhibitors; Peptide Hydrolase Inhibitors; Peptide Peptidohydrolase Inhibitors; Performance; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Pharmacology; Phase; Physiologic Availability; Piperazine, 1-(3-((1-Methylethyl)Amino)-2-Pyridinyl)-4-((5-((Methylsulfonyl)Amino)-1h-Indol-2-Yl)Carbonyl)-; Plasma; Property; Property, Loinc Axis 2; Protease Antagonists; Protease Inhibitor; Protein Binding; Proteinase Inhibitors; R01 Mechanism; R01 Program; Rna Transcriptase; Rna-Dependent Dna Polymerase; Rna-Directed Dna Polymerase; Rpg; Rat; Rattus; Relative; Relative (Related Person); Research; Research Grants; Research Project Grants; Research Projects; Research Projects, R-Series; Research Proposals; Resistance; Resistance To Multi-Drug; Resistance To Multidrug; Resistance To Multiple Drug; Resistant To Multiple Drug; Resistant To Multi-Drug; Resistant To Multidrug; Reticuloendothelial System, Serum, Plasma; Reverse Transcriptase; Reverse Transcription; Revertase; Sbir; Sbirs (R43/44); Safety; Salvage Therapy; Salvage-Tx; Science; Serum, Plasma; Small Business Innovation Research; Small Business Innovation Research Grant; Solubility; Sterilization; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Agents; Time; Toxic Effect; Toxicities; Viramune; Virion; Virus; Virus Particle; Virus-Hiv; Viruses, General; Analog; Anti-Retroviral Therapy, Highly Active; Aqueous; Base; Bioavailability Of Drug; Canine; Chemical Structure Function; Clinical Investigation; Comparative; Cost; Domestic Dog; Drug Resistant; Drug Resistant Virus; Drug/Agent; Efavirenz; Expectation; Experience; Genome Mutation; Heavy Metal Pb; Heavy Metal Lead; Human T Cell Leukemia Virus Iii; Human T Lymphotropic Virus Iii; Improved; In Vitro Assay; Inhibitor; Inhibitor/Antagonist; Meetings; Model Organism; Multi-Drug Resistant; Multidrug Resistant; Next Generation; Non-Nucleoside Rt Inhibitors; Non-Nucleoside Reverse Transcriptase Inhibitors; Nonnucleoside Reverse Transcriptase Inhibitors; Novel; Prevent; Preventing; Public Health Relevance; Resistance To Drug; Resistant; Resistant Strain; Resistant To Drug; Small Molecule; Structure Function Relationship; Virus Culture; Women Of Child Bearing Age; Women Of Childbearing Age