How Polyproline Type II Conformation at P2 Residues Influences the Success of Proline-Based Peptidyl Inhibitors Against Coronavirus Main Protease DOI
Pathum M. Weerawarna

Biochemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 30, 2024

In the wake of pandemic, peptidyl protease inhibitors with Pro-based rigid Leu mimetics at P2 position have emerged as potent drug candidates against SARS-CoV-2 main protease. This success is intuitively attributed to enhanced hydrophobic interactions and rigidity in literature. However, tertiary amide proline derivatives, which hinders formation a critical hydrogen bond enzyme active site, constrained PPII conformation, contradicts preferred β-strand represent two overlooked disadvantages associated these over traditional and, theoretically, should adversely affect their potency. Interestingly, despite major disadvantages, they maintain or display improved potency compared inhibitors. this study, we uncover previously unnoticed preference for residues adopt regardless residue identity, protease-bound form key RNA viruses, deviating from conformation. We also demonstrate that enhance binding affinity by favoring enzyme-preferred conformation significantly reducing configurational entropy loss upon binding, comparable typical bond. work highlights importance multidisciplinary approach understanding structure-activity relationships beyond medicinal chemistry intuition. believe findings provide new, deep insights address knowledge gap area inhibitor design, identifying drivers behind mere hydrophobicity.

Язык: Английский

Replication Capacity and Susceptibility of Nirmatrelvir-Resistant Mutants to Next-Generation Mpro Inhibitors in a SARS-CoV-2 Replicon System DOI Creative Commons
Chieh‐Wen Lo,

Omri Kariv,

Chenzhou Hao

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Окт. 21, 2024

Abstract There is an ongoing need to expand the anti-SARS-CoV-2 armamentarium include agents capable of suppressing replication drug-resistant mutants emerging during monotherapy with approved direct-acting antivirals. Using a subgenomic SARS-CoV-2 replicon system, we studied RNA capacity nirmatrelvir (NTV)-resistant and their susceptibility next-generation Mpro inhibitors, including ibuzatrelvir (ITV), ensitrelvir (ETV), ML2006a4. Our findings revealed that E166V reduced viral replication, whereas other mutations retained or increased capacity, suggesting potential latter dominate under NTV selective pressure. Except for having advantage against E166A mutants, ITV largely showed same mutational sensitivity as NTV. ETV was more effective than but less S144A, E166A, L167F mutants. ML2006a4 demonstrated most suppression across (S144A, E166V, S144A+L50F, E166A/V+L50F, L167F+L50F, E166A+L167F+L50F). Thus, represents attractive investigational candidate clinically relevant NTV-resistant

Язык: Английский

Процитировано

0
Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings DOI
Kathleen A. Farley, Ye Che, Ricardo Lira

и другие.

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(11), С. 2060 - 2066

Опубликована: Окт. 29, 2024

To gain further insight into the conformational properties of small cyclic peptides that bind to G-protein coupled receptor C5aR1, we report here for first time elucidation three peptide solution conformations using residual dipolar couplings and NMR temperature coefficients. Each these varies by at least one amino acid, adopts a different intramolecular hydrogen bonding pattern, has conformation. The were used in combination with homology structure C5aR1 as design template increasing potency leads C5a receptor. This study provides framework RDC guide mimetics emulate target bound state minimize strain energy conformation improve target.

Язык: Английский

Процитировано

0
Effective, but Safe? Physiologically Based Pharmacokinetic (PBPK)-Modeling-Based Dosing Study of Molnupiravir for Risk Assessment in Pediatric Subpopulations DOI Creative Commons

Sarang Mishra,

Katharina Rox

ACS Pharmacology & Translational Science, Год журнала: 2024, Номер 7(12), С. 4112 - 4122

Опубликована: Ноя. 27, 2024

Despite the end of COVID-19 pandemic, only intravenous remdesivir was approved for treatment vulnerable pediatric populations. Molnupiravir is effective against viruses beyond SARS-CoV-2 and orally administrable without CYP-interaction liabilities but has a burden potential bone or cartilage toxicity, observed at doses exceeding 500 mg/kg/day in rats. Especially, activity molnupiravir viruses, such as Ebola, with high fatality rates no option warrants exploration potentially safe populations, i.e., neonates (0-27 days), infants (1-12 months), children early childhood years). The toxicity risk these populations based on preclinical results not been systematically investigated yet. Using physiologically pharmacokinetic (PBPK) modeling, we developed adult PBPK models ranging from 50 to 1200 mg minimal parameter optimization because incorporation CES1, carboxylesterase. Therein, CES1 served main driver conversion its active metabolite

Язык: Английский

Процитировано

0
How Polyproline Type II Conformation at P2 Residues Influences the Success of Proline-Based Peptidyl Inhibitors Against Coronavirus Main Protease DOI
Pathum M. Weerawarna

Biochemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 30, 2024

In the wake of pandemic, peptidyl protease inhibitors with Pro-based rigid Leu mimetics at P2 position have emerged as potent drug candidates against SARS-CoV-2 main protease. This success is intuitively attributed to enhanced hydrophobic interactions and rigidity in literature. However, tertiary amide proline derivatives, which hinders formation a critical hydrogen bond enzyme active site, constrained PPII conformation, contradicts preferred β-strand represent two overlooked disadvantages associated these over traditional and, theoretically, should adversely affect their potency. Interestingly, despite major disadvantages, they maintain or display improved potency compared inhibitors. this study, we uncover previously unnoticed preference for residues adopt regardless residue identity, protease-bound form key RNA viruses, deviating from conformation. We also demonstrate that enhance binding affinity by favoring enzyme-preferred conformation significantly reducing configurational entropy loss upon binding, comparable typical bond. work highlights importance multidisciplinary approach understanding structure-activity relationships beyond medicinal chemistry intuition. believe findings provide new, deep insights address knowledge gap area inhibitor design, identifying drivers behind mere hydrophobicity.

Язык: Английский

Процитировано

0