Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.
Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.
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DOI：
10.1073/pnas.1806109115
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发表时间：
2018-07-17
影响因子：
11.1
通讯作者：
Lin G
中科院分区：
文献类型：
--
作者：
Kirkman LA;Zhan W;Visone J;Dziedziech A;Singh PK;Fan H;Tong X;Bruzual I;Hara R;Kawasaki M;Imaeda T;Okamoto R;Sato K;Michino M;Alvaro EF;Guiang LF;Sanz L;Mota DJ;Govindasamy K;Wang R;Ling Y;Tumwebaze PK;Sukenick G;Shi L;Vendome J;Bhanot P;Rosenthal PJ;Aso K;Foley MA;Cooper RA;Kafsack B;Doggett JS;Nathan CF;Lin G
原生动物蛋白酶体是抗疟药物开发的有效靶点，但已报道的抑制剂的物种选择性并不理想。在这里，我们确定了对疟疾蛋白酶体β5亚基的选择性优于人蛋白酶体的每个活性亚基的抑制剂。这些化合物在寄生虫生命周期的每个阶段都能杀死寄生虫。它们与β2抑制剂和青蒿素协同作用。对β5抑制剂的耐药性是通过非蛋白水解β6亚基的点突变产生的。同样的突变使突变株对β2抑制剂更敏感，更不适合承受辐射。这些发现揭示了蛋白酶体亚基之间复杂的相互作用，并介绍了联合抑制β2和β5亚基可以提供协同作用并阻止抗性的前景。我们描述了恶性疟原虫蛋白酶体（Pf20 S）β5亚基的非共价、可逆的天冬酰胺乙二胺（AsnEDA）抑制剂，该抑制剂保留了人类组成型和免疫蛋白酶体的所有活性亚基。这些化合物对红细胞期、性期和肝脏期寄生虫、对目前抗疟药耐药的寄生虫以及来自非洲患者的恶性疟原虫菌株具有活性。β5抑制剂在体外和小鼠中与β2抑制剂以及与青蒿素协同作用。令人惊讶的是，因对AsnEDA β5抑制剂耐药而被选择的恶性疟原虫在非催化β6亚基中存在点突变。β6突变体对物种选择性Pf20S β5抑制剂具有抗性，但对物种非选择性β5抑制剂硼替佐米和卡非佐米仍然敏感。此外，对Pf20S β5抑制剂的耐药性伴随着对Pf20S β2抑制剂的敏感性增加。最后，抗β5受体突变体的适应性成本会因辐射而加剧。因此，联合使用Pf20S β5和β2亚基的多阶段活性抑制剂提供协同抗疟活性，具有延迟对青蒿素和彼此耐药性出现的潜力。
Protozoal proteasome is a validated target for antimalarial drug development, but species selectivity of reported inhibitors is suboptimal. Here we identify inhibitors with improved selectivity for malaria proteasome β5 subunit over each active subunit of human proteasomes. These compounds kill the parasite in each stage of its life cycle. They interact synergistically with a β2 inhibitor and with artemisinin. Resistance to the β5 inhibitor arose through a point mutation in the nonproteolytic β6 subunit. The same mutation made the mutant strain more sensitive to a β2 inhibitor and less fit to withstand irradiation. These findings reveal complex interplay among proteasome subunits and introduce the prospect that combined inhibition of β2 and β5 subunits can afford synergy and thwart resistance. We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained sensitive to the species-nonselective β5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S β5 inhibitor was accompanied by increased sensitivity to a Pf20S β2 inhibitor. Finally, the β5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S β5 and β2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.
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影响因子：
15
作者：
Li, Hao;Tsu, Christopher;Blackburn, Christopher;Li, Gang;Hales, Paul;Dick, Lawrence;Bogyo, Matthew
通讯作者：
Bogyo, Matthew
DOI：
10.1126/science.aad3292
发表时间：
2016-01-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baym M;Stone LK;Kishony R
通讯作者：
Kishony R
影响因子：
7.3
作者：
LaMonte GM;Almaliti J;Bibo-Verdugo B;Keller L;Zou BY;Yang J;Antonova-Koch Y;Orjuela-Sanchez P;Boyle CA;Vigil E;Wang L;Goldgof GM;Gerwick L;O'Donoghue AJ;Winzeler EA;Gerwick WH;Ottilie S
通讯作者：
Ottilie S
影响因子：
82.9
作者：
Muchamuel, Tony;Basler, Michael;Groettrup, Marcus
通讯作者：
Groettrup, Marcus
影响因子：
4.2
作者：
Fan, Hao;Angelo, Nicholas G.;Lin, Gang
通讯作者：
Lin, Gang