dorsal/arxiv
View SchemaDesign of HIV-1-PR inhibitors which do not create resistance: blocking the folding of single monomers
| Authors | R. A. Broglia, G. Tiana, L. Sutto, D. Provasi, F. Simona |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0504011 |
| URL | https://arxiv.org/abs/q-bio/0504011 |
Abstract
One of the main problems of drug design is that of optimizing the drug--target interaction. In the case in which the target is a viral protein displaying a high mutation rate, a second problem arises, namely the eventual development of resistance. We wish to suggest a scheme for the design of non--conventional drugs which do not face any of these problems and apply it to the case of HIV--1 protease. It is based on the knowledge that the folding of single--domain proteins, like e.g. each of the monomers forming the HIV--1--PR homodimer, is controlled by local elementary structures (LES), stabilized by local contacts among hydrophobic, strongly interacting and highly conserved amino acids which play a central role in the folding process. Because LES have evolved over myriads of generations to recognize and strongly interact with each other so as to make the protein fold fast as well as to avoid aggregation with other proteins, highly specific (and thus little toxic) as well as effective folding--inhibitor drugs suggest themselves: short peptides (or eventually their mimetic molecules), displaying the same amino acid sequence of that of LES (p--LES). Aside from being specific and efficient, these inhibitors are expected not to induce resistance: in fact, mutations which successfully avoid their action imply the destabilization of one or more LES and thus should lead to protein denaturation. Making use of Monte Carlo simulations within the framework of a simple although not oversimplified model, which is able to reproduce the main thermodynamic as well as dynamic properties of monoglobular proteins, we first identify the LES of the HIV--1--PR and then show that the corresponding p--LES peptides act as effective inhibitors of the folding of the protease which do not create resistance.
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"abstract": "One of the main problems of drug design is that of optimizing the\ndrug--target interaction. In the case in which the target is a viral protein\ndisplaying a high mutation rate, a second problem arises, namely the eventual\ndevelopment of resistance. We wish to suggest a scheme for the design of\nnon--conventional drugs which do not face any of these problems and apply it to\nthe case of HIV--1 protease. It is based on the knowledge that the folding of\nsingle--domain proteins, like e.g. each of the monomers forming the HIV--1--PR\nhomodimer, is controlled by local elementary structures (LES), stabilized by\nlocal contacts among hydrophobic, strongly interacting and highly conserved\namino acids which play a central role in the folding process. Because LES have\nevolved over myriads of generations to recognize and strongly interact with\neach other so as to make the protein fold fast as well as to avoid aggregation\nwith other proteins, highly specific (and thus little toxic) as well as\neffective folding--inhibitor drugs suggest themselves: short peptides (or\neventually their mimetic molecules), displaying the same amino acid sequence of\nthat of LES (p--LES). Aside from being specific and efficient, these inhibitors\nare expected not to induce resistance: in fact, mutations which successfully\navoid their action imply the destabilization of one or more LES and thus should\nlead to protein denaturation. Making use of Monte Carlo simulations within the\nframework of a simple although not oversimplified model, which is able to\nreproduce the main thermodynamic as well as dynamic properties of monoglobular\nproteins, we first identify the LES of the HIV--1--PR and then show that the\ncorresponding p--LES peptides act as effective inhibitors of the folding of the\nprotease which do not create resistance.",
"arxiv_id": "q-bio/0504011",
"authors": [
"R. A. Broglia",
"G. Tiana",
"L. Sutto",
"D. Provasi",
"F. Simona"
],
"categories": [
"q-bio.BM"
],
"title": "Design of HIV-1-PR inhibitors which do not create resistance: blocking the folding of single monomers",
"url": "https://arxiv.org/abs/q-bio/0504011"
},
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