Outwitting Evolution: Fighting Drug-Resistant TB, Malaria, and HIV

Goldberg, Daniel E.; Siliciano, Robert F.; Jacobs, William R.

doi:10.1016/j.cell.2012.02.021

Cited by 161 publications

(148 citation statements)

References 109 publications

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“…Because malaria parasites contain an essential organelle of bacterial origin, the apicoplast, numerous antibacterials kill malaria parasites (1-4) and are commonly used in malaria prophylaxis or as components of multiple drug therapies (5,6). However, the emergence of multiresistant parasites compromises the efficacy of many existing chemotherapies, leading to a growing urgency for the search of new antimalarials (7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Novoa

Camacho

Tor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo.aminoacyl-tRNA synthetase | malaria | drug design | borrelidin | plasmodium

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mentioning

confidence: 99%

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Novoa

Camacho

Tor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Under such circumstances, devotion to prevention strategies, inducing adequate viral suppression and disengaging the transmission routes seem to be the optimal approaches. Taking advantage of novel resistance reporting and genotyping systems in addition to building up accessible and comprehensive databases, both locally and nationally, are also of utmost importance [71,72] . For both niches, newly invented anti-retroviral agents should be thoughtfully introduced to the host community, which would eventually thwart the emergence of resistantvirus.…”

Section: The Future Aheadmentioning

confidence: 99%

The emergence of drug resistant HIV variants and novel anti–retroviral therapy

Paydary

Khaghani

Emamzadehfard

et al. 2013

Asian Pacific Journal of Tropical Biomedicine

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“…Several pathological pathways have been contributed for this key drawback. One of the challenges in HIV/AIDS study is the possible relationships between HIV genetic penetrations and disease pathogenic progresses (human mortalities) [4][5][6].…”

Section: Current Therapeutic Limitationmentioning

confidence: 99%

“…In these initial studies, a great amount of HIV pieces can penetrate into DNA polymers as fast as 4 hrs [4]. By utility of this experimental model, a series of HIV/AIDS therapeutic agents (integrate inhibitors) have been developed and finally licensed [4][5][6][14][15][16][17].…”

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confidence: 99%

HIV in Human Genomes and Therapeutics

Lu¹,

Lü²,

Yarla³

et al. 2017

HIV Curr Res

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One of the most interesting topics in the field of HIV/AIDS study is the possible relationship between HIV genetic penetrations and disease stages. One decade before, this kind of genomic information is difficult to achieve. Yet, the innovations of next generation sequencing (NGS) have changed this landscape. At present, new generations of bio-therapies target this undesired pathogenic pathways. In this article, we address the relationships between HIV-induced genomic changes across the history and different types of therapeutics have been testified since last decade-including integrate inhibitors, genome editing agents and therapeutic schedules. Future perspectives are also given. HIV in Human Genomes and Therapeutics Knowledge EvolutionPhysical states of DNA polymers in pathologic and therapeutic studiesAt the beginning of this millennium, genomic drafting was a huge task hardly finished by single lab or even an institute. Owing to this situation, physical states of DNA samples were used to identify smallsegments of HIV genome integration into physical states of DNA polymers. In these initial studies, a great amount of HIV pieces can penetrate into DNA polymers as fast as 4 hrs [4]. By utility of this experimental model, a series of HIV/AIDS therapeutic agents (integrate inhibitors) have been developed and finally licensed [4-6,14-17].Since integrase inhibitors were usually developed by DNA polymer substrate techniques, the situation of clinical therapeutic improvements were uncertainty. It means that DNA polymer conditions are not completely parallel with complicate conditions in living cells and bodies-including HIV infected patients. As a result, more sophisticate living conditions (in vitro or in vivo experimental models) must be established, and even utilized as HIV therapeutic drug evaluating systems. Different types of animal models and human cell modelsBefore clinical human genomic pathological and therapeutic studies, in vitro or in vivo animal models for HIV genomic integration must be utilized first. In animal model studies, selections of animal genomic origin and human cell/tissue types are important.There are similarity and diversity among different animal genomic origins and human cell types. These types of animal/human genomic studies generally needs less ethical requirements and can be studied in repeat ways comparing with clinical human investigations. In our opinions, these types of HIV genomic penetration studies should be emphasized now and in future. Similarly, these types of HIV animal

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Outwitting Evolution: Fighting Drug-Resistant TB, Malaria, and HIV

Cited by 161 publications

References 109 publications

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

The emergence of drug resistant HIV variants and novel anti–retroviral therapy

HIV in Human Genomes and Therapeutics

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