Stephen C. Pelly
The field of medicinal chemistry is a particularly rewarding research area as it requires expertise from several diverse backgrounds for a successful research project. Our main research focus is developing anti-HIV compounds, with a specific interest in designing and synthesizing non-nucleoside reverse transcriptase inhibitors and integrase strand transfer inhibitors. To this end we incorporate a significant amount of molecular modelling in the design phases of the project in order to identify novel promising compounds which are synthesized to establish proof of concept. Once this has been accomplished, we embark upon a more extensive synthetic campaign to accumulate SAR data which in turn provides valuable guidance for the ongoing modelling phase of the project, thus leading to optimized compounds in an iterative rational design process. This research is particularly relevant in a South African context, given the enormous social and economic problems we face as a result of a particularly high prevalence of the disease in our country, and indeed, sub-Saharan Africa in general.
This research is made possible by well-equipped laboratories with access to all the required spectroscopic services (in particular, NMR, mass spectrometry and single crystal X-ray diffractometry) as well as modern molecular modeling facilities. Collaborations with groups (both national and international) provides the expertise in areas such as whole cell and enzymatic assays, which are so critical to the overall success of the projects.
Current Projects in HIV Drug Design:
In this, our longest running and most successful project, the indole system has been utilised as an effective scaffold for the design and development of novel, potent, HIV NNRTIs. The initial design emanated from modelling studies, and incorporated a cyclopropyl ring system suitably attached to the indole such that this small hydrophobic functional group occupied the Val179 pocket. This initial concept resulted in the first hit compounds in this series, being moderate inhibitors of HIV right from the start.
The design then evolved to methyl ether derivatives which were highly potent inhibitors of HIV replication for both the wild type strain of the virus, and the problematic K103N resistant strain. Unfortunately however, these compounds were not stable under acidic conditions. Replacement of the methyl ether with a methyl sulphide solved the acid lability problem, whilst maintaining high efficacy against the virus. Work continues in this project as we determine which enantiomer is the most effective inhibitor, and we suitably functionalise the periphery to enhance efficacy against resistant strains of the virus.
We were inspired by the pyrazole NNRTI Lersivirine, itself originating from the earlier NNRTI Capravirine. LSV is a potent NNRTI which is effective against wild type HIV at low nano-molar concentrations and more importantly, is effective against several problematic mutant strains of the virus, especially the K103N and Y181C mutants where only a marginal decrease in potency is observed. Unfortunately, continued development of LSV was halted recently at the end of phase IIB clinical trials. Nevertheless, the small five membered heterocyclic pyrazole ring serving as a hub for various substituents intrigued us and we were curious as to whether other rings systems could be utilised or this purpose, especially those easily accessible by multi-component coupling reactions. Of particular interest was whether the pyrazole ring could be substituted by a triazole ring, given the versatility in obtaining these systems by way of the Cu(I) catalysed 'click' reaction. In this project, variously substituted triazole systems are bing investigated as potential new and easily accessible HIV NNRTIs.
Many NNRTIs depend on strong Pi interactions with the aromatic side chain of Tyr181. Although this has proven an effective strategy in the design of inhibitors for wilt type and several mutant variants of the virus, the Y181C mutation usually obliterates the potency of these compounds. In this project, through a careful rational design process, we have purposefully avoided interactions with Tyr181, focussing instead on interactions with Tyr188 and more importantly, the conserved residue, Trp229. This strategy has resulted in the synthesis of several low nanomolar inhibitors, effective against the Y181C resistant strain. Work continues in the project, with the emphasis being on developing inhibitors effective against double mutant variants of the virus.
First line treatment for HIV usually consists of a combination of three drug actives and is referred to as highly active antiretroviral therapy (HAART). Although this polypharmacy approach has proven to be very effective as a front line treatment by providing a higher barrier to the development of resistance and allowing for reduced doses, long term treatment with a cocktail of drugs unfortunately still presents ongoing challenges such as long term toxicity, multidrug resistance and of course, the cost of producing a tablet containing multiple APIs. Of particular interest to current anti-HIV research is that the RNase H site of HIV reverse transcriptase (RT) is very similar to that of the catalytic core domain of HIV integrase (IN). Indeed, both of these enzymes belong to a larger superfamily of polynucleotidyl transferases. This project aims to expand our HIV research program into the area of dual-target inhibitors, with one API pharmacophore capable of targeting both HIV IN and HIV RT at the RNase H pocket. Currently, there are no licensed antiretrovirals which operate via this mechanism, and in fact, the RT RNase H pocket itself is currently not exploited in HIV therapy. Through a rational design approach, we aim to exploit the similarity in these two pockets to design and synthesise potent dual-target antiretrovirals.
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