Targeting Drug Resistant Mutations Using Novel Binding Interactions - Lessons Learned from Abl-T315I and their Implications in D

Noronha, Glen; Cao, Jian; Chow, Chun P.; Dneprovskaia, Elena; Hwang, Linda; Lohse, Dan; Mak, Chi Ching; McPherson, Andrew; Fine, Richard M.; Kang, Xinshan; Klebansky, Boris; Palanki, Moorthy S. S.; Pathak, V. P.; Renick, Joel; Söll, Richard; Zeng, Binqi

doi:10.2174/978160805201110703010121

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“…It now becomes clearer that future antiviral strategies should address this issue from the outset, aggressively striving to prevent viral escape. To deal with this, several directions have been explored since a decade: the structures of resistant proteins [ 3 ], second generation drugs that can bind resistant proteins [ 4 ], drug target polymorphism analysis in order to define "super drugs" [ 5 ], definition of new targets, such as protein backbones [ 6 ] or dimeric proteins' monomers, in order to block them before dimerisation [ 7 ]. Overall, although individual case solutions were found, no general solution has emerged yet.…”

Section: Introductionmentioning

confidence: 99%

Co-lethality studied as an asset against viral drug escape: the HIV protease case

Brouillet

Valere²,

Ollivier

et al. 2010

Biol Direct

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BackgroundCo-lethality, or synthetic lethality is the documented genetic situation where two, separately non-lethal mutations, become lethal when combined in one genome. Each mutation is called a "synthetic lethal" (SL) or a co-lethal. Like invariant positions, SL sets (SL linked couples) are choice targets for drug design against fast-escaping RNA viruses: mutational viral escape by loss of affinity to the drug may induce (synthetic) lethality.ResultsFrom an amino acid sequence alignment of the HIV protease, we detected the potential SL couples, potential SL sets, and invariant positions. From the 3D structure of the same protein we focused on the ones that were close to each other and accessible on the protein surface, to possibly bind putative drugs. We aligned 24,155 HIV protease amino acid sequences and identified 290 potential SL couples and 25 invariant positions. After applying the distance and accessibility filter, three candidate drug design targets of respectively 7 (under the flap), 4 (in the cantilever) and 5 (in the fulcrum) amino acid positions were found.ConclusionsThese three replication-critical targets, located outside of the active site, are key to our anti-escape strategy. Indeed, biological evidence shows that 2/3 of those target positions perform essential biological functions. Their mutational variations to escape antiviral medication could be lethal, thus limiting the apparition of drug-resistant strains.ReviewersThis article was reviewed by Arcady Mushegian, Shamil Sunyaev and Claus Wilke.

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