ZIA BC 007363 (ZIA) | |||
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Title | Design and Synthesis of HIV Integrase as Potential Anti-AIDS Drugs | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Burke, Terrence | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $245,217 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Kaposi Sarcoma (50.0%) Sarcoma (50.0%) |
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Research Type | |||
Localized Therapies - Discovery and Development Systemic Therapies - Discovery and Development |
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Abstract | |||
Inhibitors of HIV-1 integrase (IN) inhibitors represent the most recent anti-AIDS drugs. Merck's raltegravir (RAL) (October 2007) and Gilead's elvitegravir (EVG) (August 2012) were the first two IN inhibitors to be approved by the FDA. These agents are members of a class of drugs called ""IN strand transfer inhibitors"" (INSTIs), due to their ability to preferentially block the enzyme's strand transfer (ST) reaction as compared to the enzymes 3'-processing (3'-P) reaction. Treatment with RAL and EVG selects for resistant forms of HIV and there is considerable cross-resistance to these two drugs. GlaxoSmithKline's dolutegravir (DTG) was approved by the FDA in August of 2013 as a 2nd-generation INSTI having improved efficacies against RAL and EVG-resistant strains of HIV. However, DTG also selects for resistant strains of HIV, emphasizing the need for continued development of agents that can overcome resistant strains of IN, including the emerging DTG-resistant strains. Utilizing my laboratory's design and synthetic capabilities, we have teamed with pharmacologists (Dr. Yves Pommier, NCI), virologists (Dr. Hughes, NCI) and structural biologists (Dr. Cherepanov, London Research Institute) to develop new IN inhibitors. DTG is characterized by an extended tricyclic system, in which the third ring is known to be important, but the underlying reasons for this are poorly understood. We elaborated the core of our bicyclic 7,8-dihydroxy-3,4-dihydroisoquinolin-1(2H)-one based HIV-1 integrase inhibitors platform into the region IN catalytic site that is occupied by DTG's third ring and we found that appropriately tethering oxygen functionality at the 6-position improved inhibitory profiles. The potencies of these compounds equal or exceed those of DTG across an entire large panel of 18 single, 11 double and 6 triple HIV mutants, which represent the major INSTI-resistant forms. In collaboration with Dr. Cherepanov we obtained co-crystal structures of our best inhibitors bound to the prototype foamy virus (PFV) intasome (multimeric integrase with DNA substrate and metal cofactor). We found that there are overlaps in aspects of the 6-side chains that coincide with both unprocessed viral DNA in a pre-3'-P complex and the target DNA in a ST complex. We realized that this represents an unusual form of ""bi-substrate"" mimicry. It exemplifies the more general concept of ""substrate envelope,"" originally used to explain why some HIV protease inhibitors are able to retain efficacy against multiple resistance mutations. We found similar components of bi-substrate mimicry in other potent INSTIs having good profiles against resistant mutant forms of IN. This work has led us to postulate the general concept that substrate mimicry and substrate envelope may be broadly applicable in the design of INSTIs endowed with an ability to retain efficacy against resistant mutant forms of IN. Of note: This provides general guiding rationale for designing INSTIs that circumvent resistant mutant forms of IN. Most recently, we have identified additional substituents at the 6-position that are highly effective, with the best compound retaining better efficacy against the broad panel of known INSTI resistant mutants than any analogs we have previously described. Separately, we have begun investigating inhibitors of the polymerase (Pol) and RNase H domains of HIV- 1 reverse transcriptase (RT). Both RT and IN are members of a superfamily of polynucleotidyl transferases that use divalent metal cofactors. RT has two catalytic centers, a DNA polymerase (Pol) and an RNase H that cleaves RNA if it is part of an RNA-DNA duplex. These two activities collaborate to produce, from single-stranded genomic RNA, a double-stranded DNA that is the substrate for IN. At this time, there are no FDA-approved HIV-1 RNase H inhibitors and it remains as one of the last unutilized targets for AIDS therapeutics. Collateral cytotoxicity is a significant limitation of current RNase H inhibitors and a |