More Like this

1. Development of Natural‐Product‐Inspired ABCB1 Inhibitors Through Regioselective Tryptophan C3‐Benzylation

   https://doi.org/10.1002/chem.202401782  

   Mariya_Vincent, Dona; Mostafa, Habib; Suneer, Anza; Radha_Krishnan, Sabhashina; Ong, Mingmin; Itahana, Yoko; Itahana, Koji; Viswanathan, Rajesh (October 2024, Chemistry – A European Journal)

   Abstract The emergence of drug resistance in cancer cells eventually causing relapse is a serious threat that demands new advances. Upregulation of the ATP‐dependent binding cassette (ABC) transporters, such as ABCB1, significantly contributes to the emergence of drug resistance in cancer. Despite more than 30 years of therapeutic discovery, and several generations of inhibitors against P‐gp, the search for effective agents that minimize toxicity to human cells, while maintaining efflux pump inhibition is still underway. Leads derived from natural product scaffolds are well‐known to be effective in various therapeutic approaches. Inspired by the biosynthetic pathway to Nocardioazine A, a marine alkaloid known to inhibit the P‐gp efflux pump in cancer cells, we devised a regioselective pathway to create structurally unique indole‐C3‐benzylcyclo‐L‐Trp‐L‐Trp diketopiperazines (DKPs). Using bat cells as a model to derive effective ABCB1 inhibitors for targeting human P‐gp efflux pumps, we have recently identifiedexo‐C3‐N‐Dbn‐Trp2 (13)as a lead ABCB1 inhibitor. This C3‐benzylated lead inhibited ABCB1 better than Verapamil.^[21]Additionally,C3‐N‐Dbn‐Trp2restored chemotherapy sensitivity in drug‐resistant human cancer cells and had no adverse effect on cell proliferation in cell cultures. For a clearer structure‐activity relationship, we developed a broader screen to test C3‐functionalized pyrroloindolines as ABCB1 inhibitors and observed that C3‐benzylation is outperforming respective isoprenylated derivatives. Results arising from the molecular docking studies indicate that the interactions at the access tunnel between ABCB1 and the inhibitor result in a powerful predictor for the efficacy of the inhibitor. Based on fluorescence‐based assays, we conclude that the most efficacious inhibitor is thep‐cyano‐derivedexo‐C3‐N‐Dbn‐Trp2 (33 a), closely followed by thep‐nitro substituted analogue. By combining assay results with molecular docking studies, we further correlate that the predictions based on the inhibitor interactions at the access tunnel provide clues about the design of improved ABCB1 inhibitors. As it has been well documented that ABCB1 itself is powerfully engaged in multi‐drug resistance, this work lays the foundation for the design of a new class of inhibitors based on the endogenous amino acid‐derivedcyclo‐L‐Trp‐L‐Trp DKP scaffold. 

   more » « less
2. Microfluidic bioassay to characterize parasitic nematode phenotype and anthelmintic resistance

   https://doi.org/10.1017/S0031182010001010  

   CHEN, BAOZHEN; DEUTMEYER, ALEX; CARR, JOHN; ROBERTSON, ALAN P.; MARTIN, RICHARD J.; PANDEY, SANTOSH (January 2011, Parasitology)

   SUMMARY With increasing resistance to anti-parasitic drugs, it has become more important to detect and recognize phenotypes of resistant isolates. Molecular methods of detecting resistant isolates are limited at present. Here, we introduce a microfluidic bioassay to measure phenotype using parameters of nematode locomotion. We illustrate the technique on larvae of an animal parasite Oesophagostomum dentatum. Parameters of sinusoidal motion such as propagation velocity, wavelength, wave amplitude, and oscillation frequency depended on the levamisole-sensitivity of the isolate of parasitic nematode. The levamisole-sensitive isolate (SENS) had a mean wave amplitude of 135 μ m, which was larger than 123 μ m of the levamisole-resistant isolate (LEVR). SENS had a mean wavelength of 373 μ m, which was less than 393 μ m of LEVR. The mean propagation velocity of SENS, 149 μ m s −1 , was similar to LEVR, 143 μ m s −1 . The propagation velocity of the isolates was inhibited by levamisole in a concentration-dependent manner above 0·5 μ m . The EC 50 for SENS was 3 μ m and the EC 50 for LEVR was 10 μ m . This microfluidic technology advances present-day nematode migration assays and provides a better quantification and increased drug sensitivity. It is anticipated that the bioassay will facilitate study of resistance to other anthelmintic drugs that affect locomotion. 

   more » « less
3. Targeting STAT3 anti-apoptosis pathways with organic and hybrid organic–inorganic inhibitors

   https://doi.org/10.1039/C9OB02682G  

   Minus, Matthew B.; Wang, Haopei; Munoz, Jaime O.; Stevens, Alexandra M.; Mangubat-Medina, Alicia E.; Krueger, Michael J.; Liu, Wei; Kasembeli, Moses M.; Cooper, Julian C.; Kolosov, Mikhail I.; et al (May 2020, Organic & Biomolecular Chemistry)

   Recurrence and drug resistance are major challenges in the treatment of acute myeloid leukemia (AML) that spur efforts to identify new clinical targets and active agents. STAT3 has emerged as a potential target in resistant AML, but inhibiting STAT3 function has proven challenging. This paper describes synthetic studies and biological assays for a naphthalene sulfonamide inhibitor class of molecules that inhibit G-CSF-induced STAT3 phosphorylation in cellulo and induce apoptosis in AML cells. We describe two different approaches to inhibitor design: first, variation of substituents on the naphthalene sulfonamide core allows improvements in anti-STAT activity and creates a more thorough understanding of anti-STAT SAR. Second, a novel approach involving hybrid sulfonamide–rhodium( ii ) conjugates tests our ability to use cooperative organic–inorganic binding for drug development, and to use SAR studies to inform metal conjugate design. Both approaches have produced compounds with improved binding potency. In vivo and in cellulo experiments further demonstrate that these approaches can also lead to improved activity in living cells, and that compound 3aa slows disease progression in a xenograft model of AML. 

   more » « less
4. Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors

   https://doi.org/10.1038/s42004-024-01225-z  

   Koh, Javier_Yu Peng; Itahana, Yoko; Krah, Alexander; Mostafa, Habib; Ong, Mingmin; Iwamura, Sahana; Vincent, Dona Mariya; Radha_Krishnan, Sabhashina; Ye, Weiying; Yim, Pierre_Wing Chi; et al (July 2024, Communications Chemistry)

   Abstract Chemotherapy-induced drug resistance remains a major cause of cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylatedCyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers. 

   more » « less
5. Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

   https://doi.org/10.1039/D0SC04942E  

   Pavlova, Anna; Lynch, Diane L.; Daidone, Isabella; Zanetti-Polzi, Laura; Smith, Micholas Dean; Chipot, Chris; Kneller, Daniel W.; Kovalevsky, Andrey; Coates, Leighton; Golosov, Andrei A.; et al (February 2021, Chemical Science)

   The main protease (M pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M pro , a cysteine protease, have been determined, facilitating structure-based drug design. M pro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41–Cys145, M pro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nucleophile Cys145 have been debated in previous studies of SARS-CoV M pro , but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 M pro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of M pro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored N δ (HD) and N ϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 M pro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts. 

   more » « less