Generative artificial intelligence performs rudimentary structural biology modeling DOI Creative Commons
Alexander M. Ille, Christopher Markosian, S.K. Burley

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Авг. 21, 2024

Natural language-based generative artificial intelligence (AI) has become increasingly prevalent in scientific research. Intriguingly, capabilities of pre-trained transformer (GPT) language models beyond the scope natural tasks have recently been identified. Here we explored how GPT-4 might be able to perform rudimentary structural biology modeling. We prompted model 3D structures for 20 standard amino acids and an α-helical polypeptide chain, with latter incorporating Wolfram mathematical computation. also used interaction analysis between anti-viral nirmatrelvir its target, SARS-CoV-2 main protease. Geometric parameters generated typically approximated close experimental references. However, modeling was sporadically error-prone molecular complexity not well tolerated. Interaction further revealed ability identify specific acid residues involved ligand binding along corresponding bond distances. Despite current limitations, show capacity AI basic atomic-scale accuracy.

Язык: Английский

Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model DOI Open Access
Bin Tan, Xiaoming Zhang, Ahmadullah Ansari

и другие.

Science, Год журнала: 2024, Номер 383(6690), С. 1434 - 1440

Опубликована: Март 28, 2024

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. papain-like protease (PL pro ) is a promising but challenging drug target. We designed synthesized 85 noncovalent PL inhibitors that bind to recently discovered ubiquitin binding site the known BL2 groove pocket near S4 subsite. Leads inhibited with inhibitory constant K i values from 13.2 88.2 nanomolar. co-crystal structures eight leads revealed their interaction modes. in vivo lead Jun12682 its variants, including nirmatrelvir-resistant strains EC 50 0.44 2.02 micromolar. Oral treatment improved survival reduced lung viral loads lesions infection mouse model, suggesting are antiviral candidates.

Язык: Английский

Процитировано

47
Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants DOI Creative Commons
Daniele Focosi, Arturo Casadevall, Massimo Franchini

и другие.

Viruses, Год журнала: 2024, Номер 16(2), С. 217 - 217

Опубликована: Янв. 31, 2024

Among the anti-Spike monoclonal antibodies (mAbs), S-309 derivative sotrovimab was most successful in having longest temporal window of clinical use, showing a high degree resiliency to SARS-CoV-2 evolution interrupted only by appearance BA.2.86* variant interest (VOI). This success undoubtedly reflects rational selection target highly conserved epitope coronavirus Spike proteins. We review here efficacy against different variants outpatients and inpatients, discussing both randomized controlled trials real-world evidence. Although it could not be anticipated at time its development introduction, sotrovimab's use immunocompromised individuals who harbor large populations viruses created conditions for eventual demise, as antibody viral led withdrawal due inefficacy later lineages. Despite this, based on observational data, some authorities have continued promote sotrovimab, but lack binding newer strongly argues futility use. The story highlights power modern biomedical science generate novel therapeutics while also providing cautionary tale need devise strategies minimize emergence resistance antibody-based therapeutics.

Язык: Английский

Процитировано

19
SARS-CoV-2 Drug Resistance and Therapeutic Approaches DOI Creative Commons

Sania Batool,

Santosh Chokkakula, Ju Hwan Jeong

и другие.

Heliyon, Год журнала: 2025, Номер 11(2), С. e41980 - e41980

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

3
In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance DOI Creative Commons
Yuao Zhu, Irina Yurgelonis, Stephen Noell

и другие.

Science Advances, Год журнала: 2024, Номер 10(30)

Опубликована: Июль 24, 2024

To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against virus M

Язык: Английский

Процитировано

15
Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections DOI Creative Commons
Mohammed Nooruzzaman, Katherine Johnson, Ruchi Rani

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 18, 2024

Язык: Английский

Процитировано

14
An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations DOI
Michael Westberg, Yichi Su, Xinzhi Zou

и другие.

Science Translational Medicine, Год журнала: 2024, Номер 16(738)

Опубликована: Март 13, 2024

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing severity COVID-19, but presence resistance-conferring mutations sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized covalent hepatitis C virus inhibitor boceprevir (BPV) could serve basis for orally bioavailable inhibit SARS-CoV-2 M more efficiently than existing drugs. Performing structure-guided modifications BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, pharmacokinetics, therapeutic efficacy similar or superior to those NTV. A crucial feature ML2006a4 is derivatization ketoamide reactive group improves cell permeability bioavailability. Last, was found be less sensitive several cause resistance NTV ETV occur natural population. Thus, anticipatory design can preemptively address potential mechanisms expand treatment options variants.

Язык: Английский

Процитировано

12
COVID-19 therapeutics DOI
Daniele Focosi, Massimo Franchini, Fabrizio Maggi

и другие.

Clinical Microbiology Reviews, Год журнала: 2024, Номер 37(2)

Опубликована: Май 21, 2024

SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy those often remains controversial or compromised by viral evolution. Uncertainties still persist regarding best therapies for high-risk patients, drug pipeline is suffering fatigue shortage funding. In this article, we review antiviral activity, mechanism action, pharmacokinetics, safety therapies. Additionally, summarize evidence from randomized controlled trials on various antivirals discuss unmet needs which should be addressed.

Язык: Английский

Процитировано

12
SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs DOI Creative Commons
Sho Iketani, David D. Ho

Cell chemical biology, Год журнала: 2024, Номер 31(4), С. 632 - 657

Опубликована: Апрель 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Язык: Английский

Процитировано

9
Emerging SARS-CoV-2 Resistance After Antiviral Treatment DOI Creative Commons

Trevor J M Tamura,

Manish C. Choudhary,

Rinki Deo

и другие.

JAMA Network Open, Год журнала: 2024, Номер 7(9), С. e2435431 - e2435431

Опубликована: Сен. 25, 2024

Importance Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this arises and its association with posttreatment virologic rebound is not well understood. Objective To examine the prevalence of emergent antiviral after nirmatrelvir treatment rebound. Design, Setting, Participants This cohort study enrolled outpatient adults acute COVID-19 infection from May 2021 October 2023. were divided into those who received therapy did not. The was conducted at a multicenter health care system Boston, Massachusetts. Exposure Treatment regimen, including none, remdesivir. Main Outcomes Measures primary outcome resistance, defined as detection mutations, which present baseline, previously associated decreased efficacy, emerged during or completion participant’s treatment. Next-generation sequencing used detect low frequency down 1% total viral population. Results Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) included. Compared 63 untreated individuals, 79 older more commonly immunosuppressed. After RNA participants’ anterior nasal swabs, detected 9 individuals (11.4%) compared 2 (3.2%) ( P = .09). Among treated immunosuppressed had highest emergence (5 22 [22.7%]), significantly greater than (2 [3.1%]) .01). Similar rates found (3 23 [13.0%]) vs (6 [10.7%]) .86). Most these (10 11 [90.9%]) frequencies (<20% population) reverted wild type subsequent time points. Emerging remdesivir only 14 [14.3%]) but similarly transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence increased United States authorization nirmatrelvir. Conclusions Relevance In participants, treatment-emergent detected, especially However, generally transient nature, suggesting risk for spread community current variants drug usage patterns.

Язык: Английский

Процитировано

8
Distal protein-protein interactions contribute to nirmatrelvir resistance DOI Creative Commons
Eric M. Lewandowski, Xiujun Zhang, Haozhou Tan

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 1, 2025

SARS-CoV-2 main protease, Mpro, is responsible for processing the viral polyproteins into individual proteins, including protease itself. Mpro a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component Paxlovid). Resistance mutants identified clinically and in passage assays contain combination site mutations (e.g., E166V, E166A, L167F), which reduce inhibitor binding enzymatic activity, non-active P252L, T21I, L50F), restore fitness replication. To probe role rescue, here we use an triple mutant (L50F/E166A/L167F) that confers drug resistance with level similar to wild-type. By comparing peptide full-length protein substrates, demonstrate substrate involves more than residues site. Particularly, L50F other can enhance dimer-dimer interactions help place nsp5-6 at enzyme catalytic center. The structural activity data L50F, L50F/E166A/L167F, others underscore importance considering whole studying interactions, offers important insights function, development, design.

Язык: Английский

Процитировано

1