Deuterium in drug discovery: progress, opportunities and challenges

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(7), С. 562 - 584

Опубликована: Июнь 5, 2023

Язык: Английский

---

Small molecules in the treatment of COVID-19

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Дек. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Язык: Английский

---

Oral antiviral treatments for COVID-19: opportunities and challenges

Pharmacological Reports, Год журнала: 2022, Номер 74(6), С. 1255 - 1278

Опубликована: Июль 25, 2022

The use of antiviral COVID-19 medications can successfully inhibit SARS-CoV-2 replication and prevent disease progression to a more severe form. However, the timing treatment plays crucial role in this regard. Oral drugs provide an opportunity manage infection without need for hospital admission, easing general burden that have on healthcare system. This review paper (i) presents potential pharmaceutical targets, including various host-based targets viral-based (ii) characterizes first-generation anti-SARS-CoV-2 oral (nirmatrelvir/ritonavir molnupiravir), (iii) summarizes clinical progress other antivirals COVID-19, (iv) discusses ethical issues such trials (v) challenges associated with practice. represent part strategy adapt long-term co-existence manner prevents from being overwhelmed. It is pivotal ensure equal fair global access currently available those authorized future.

Язык: Английский

---

Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 257, С. 115503 - 115503

Опубликована: Май 18, 2023

Язык: Английский

---

A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Март 16, 2023

Abstract Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten global public health. Small molecule antivirals are an effective treatment strategy to fight against virus. However, first-generation either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across globe, they face great pressure drug resistance. We herein present discovery characterization a new generation antiviral candidate (SY110), which is potent selective inhibitor main protease (M pro ). This compound displayed vitro activity not only predominant sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 MERS-CoV. In Omicron-infected K18-hACE2 mouse model, oral SY110 significantly lowered viral burdens lung alleviated virus-induced pathology. Importantly, possesses favorable PK properties high exposure bioavailability, outstanding safety profile. Furthermore, exhibited sensitivity several drug-resistance M mutations. Collectively, this investigation provides promising variants SARS-CoV-2.

Язык: Английский

---

Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 260, С. 115772 - 115772

Опубликована: Авг. 28, 2023

Язык: Английский

---

Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir

Nature Microbiology, Год журнала: 2024, Номер 9(4), С. 1075 - 1088

Опубликована: Март 29, 2024

Abstract Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir still needed, particularly individuals in whom less effective, the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of SARS-CoV-2 main protease (M pro ), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has constant 8.4 nM and suggests it dissociates about 12 times slower from M compared with nirmatrelvir. The crystal structure :RAY1216 complex covalently binds catalytic Cys145 through α-ketoamide group. In vitro using human ACE2 transgenic mouse models, activities against variants comparable those It also improved pharmacokinetics mice rats, suggesting could be used without ritonavir, which is co-administered been approved a single-component drug named ‘leritrelvir’ COVID-19 treatment China.

Язык: Английский

---

COVID-19 drug discovery and treatment options

Nature Reviews Microbiology, Год журнала: 2024, Номер 22(7), С. 391 - 407

Опубликована: Апрель 15, 2024

Язык: Английский

---

Discovery of The Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 28, 2025

Abstract The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health an unmet need for options. Herein, we report the discovery of S-892216 , a second-generation SARS-CoV-2 3C-like protease (3CL pro ) inhibitor, treat COVID-19. is reversible covalent 3CL inhibitor with highly potent antiviral activity EC 50 value 2.48 nM against infected cells. Structure-based design modifier compound 1 revealed that introducing nitrile warhead increased inhibition 180-fold. Subsequent optimization yielded which combined favorable pharmacokinetic profile high off-target selectivity. exhibited diverse variants, no cross-resistance major mutations reducing activities nirmatrelvir ensitrelvir. In SARS-CoV-2-infected mice, inhibited viral replication in lungs similar ensitrelvir, although at 30-fold lower dose.

Язык: Английский

---

SARS-CoV-2 Main Protease Drug Design, Assay Development, and Drug Resistance Studies

Accounts of Chemical Research, Год журнала: 2022, Номер 56(2), С. 157 - 168

Опубликована: Дек. 29, 2022

ConspectusSARS-CoV-2 is the etiological pathogen of COVID-19 pandemic, which led to more than 6.5 million deaths since beginning outbreak in December 2019. The unprecedented disruption social life and public health caused by calls for fast-track development diagnostic kits, vaccines, antiviral drugs. Small molecule antivirals are essential complements vaccines can be used treatment SARS-CoV-2 infections. Currently, there three FDA-approved drugs, remdesivir, molnupiravir, paxlovid. Given moderate clinical efficacy remdesivir drug–drug interaction paxlovid, emergence variants with potential drug-resistant mutations, a pressing need additional combat current future coronavirus outbreaks.In this Account, we describe our efforts developing covalent noncovalent main protease (Mpro) inhibitors identification nirmatrelvir-resistant mutants. We initially discovered GC376, calpain II XII, boceprevir as dual Mpro host cathepsin L from screening inhibitor library. controversy targeting L, subsequently shifted focus designing Mpro-specific inhibitors. Specifically, guided X-ray crystal structures these initial hits, designed such Jun8-76-3R that highly selective toward over L. Using same scaffold, also novel cysteine reactive warheads containing di- trihaloacetamides, similarly had high target specificity. In parallel drug discovery efforts, developed cell-based FlipGFP assay characterize cellular engagement rationally was applied validate structurally disparate reported literature. Lastly, introduce recent progress identifying naturally occurring mutants resistant nirmatrelvir genome mining nsp5 sequences deposited GISAID database. Collectively, hot spot residues studies provide insightful guidance work aimed at orally bioavailable do not have overlapping resistance profile nirmatrelvir.

Язык: Английский

---