Received: November 15, 2023/ Accepted: November 17, 2023/ Published online: December 28, 2023
УДК 615.035.1
DOI: 10.26212/2227-1937.2023.19.64.019
I.R. Fakhradiyev, ORCID: http://orcid:0000-0003-0528-3874
T.M. Saliev, ORCID: http://orcid:0000-0001-5696-6363
Sh.B. Tanabayeva, ORCID: http://orcid:0000-0003-1826-0460
T.R. Fazylov, ORCID: http://orcid:0000-0001-9604-5155
M.B. Kulimbet, ORCID: http://orcid:0000-0003-4399-700X
K.A. Muratova, ORCID: http://orcid:0009-0001-7011-9213
N.S. Ahmad, ORCID: http://orcid:0000-0002-7180-2006
K.B. Abdykerimova, ORCID: http://orcid:0009-0007-6384-0241
A.M. Orazymbetova, ORCID: http://orcid:0009-0002-0187-4220
S.D. Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
LITERATURE REVIEW: PROTEASE INHIBITORS AS PROMISING AGENTS IN THE FIGHT AGAINST COVID-19 – EVALUATION OF ANTIVIRAL ACTIVITY
Resume:
Background: The COVID-19 pandemic has necessitated an urgent search for effective therapeutics. Protease inhibitors have
gained considerable attention as potential antiviral agents against SARS-CoV-2. This literature review aims to evaluate the
current state of research on the antiviral activity of protease inhibitors against SARS-CoV-2, focusing on their mechanism of
action, in-vitro efficacy, clinical trial findings, and issues related to drug resistance and side effects.
Methods: A comprehensive search was conducted across multiple databases, including PubMed, Scopus, and Google Scholar,
using relevant keywords. A total of 22 studies, comprising various research designs, were included in the review.
Results: Protease inhibitors effectively target key viral enzymes, demonstrating strong binding affinities. In-vitro studies
generally indicate a broad-spectrum efficacy against SARS-CoV-2. However, clinical trials have shown mixed results, with
some studies indicating significant benefits, while others do not. Side effects are common but generally manageable. The
likelihood of drug resistance remains relatively low but is a potential concern.
Conclusion: Protease inhibitors hold promise as antiviral agents against SARS-CoV-2 due to their robust mechanisms of
action and in-vitro efficacy. However, clinical utility remains a matter of ongoing debate. Further research, particularly longterm and multi-center trials, are essential to fully establish the role of protease inhibitors in COVID-19 treatment. Issues
related to drug resistance and side effects need to be carefully considered. Overall, protease inhibitors could serve as a
valuable component of a multi-pronged therapeutic approach against COVID-19.
Keywords: COVID-19, SARS-CoV-2, Protease Inhibitors, Antiviral Activity, Clinical Trials, Drug Resistance.
REFERENCES
1 Aggarwal NR, Molina KC, Beaty LE, Bennett TD, Carlson
NE, Mayer DA, et al. Real-world use of nirmatrelvir–
ritonavir in outpatients with COVID-19 during the era of
omicron variants including BA.4 and BA.5 in Colorado,
USA: a retrospective cohort study. Lancet Infect Dis
[Internet]. 2023;23(6):696–705. Available from:
http://dx.doi.org/10.1016/s1473-3099(23)00011-7
2 Alves VM, Bobrowski T, Melo-Filho CC, Korn D,
Auerbach S, Schmitt C, et al. QSAR modeling of SARS‑CoV
Mpro inhibitors identifies sufugolix, cenicriviroc,
proglumetacin, and other drugs as candidates for
repurposing against SARS‑CoV‑2. Mol Inform [Internet].
2021;40(1). Available from:
http://dx.doi.org/10.1002/minf.202000113
3 Brown L-AK, Freemantle N, Breuer J, Dehbi H-M,
Chowdhury K, Jones G, et al. Early antiviral treatment in
outpatients with COVID-19 (FLARE): a structured
summary of a study protocol for a randomised controlled
trial. Trials [Internet]. 2021;22(1). Available from:
http://dx.doi.org/10.1186/s13063-021-05139-2
4 Cao Z, Gao W, Bao H, Feng H, Mei S, Chen P, et al. VV116
versus nirmatrelvir–ritonavir for oral treatment of covid19. N Engl J Med [Internet]. 2023;388(5):406–17.
Available from:
http://dx.doi.org/10.1056/nejmoa2208822
5 Caso JM, Fernández-Ruiz M, López-Medrano F, CaroTeller JM, Lizasoain M, San-Juan R, et al.
Nirmatrelvir/ritonavir for the treatment of
immunocompromised adult patients with early‑stage
symptomatic COVID‑19: A real‑life experience. J Med Virol
[Internet]. 2023;95(9). Available from:
http://dx.doi.org/10.1002/jmv.29082
6 Gentry CA, Nguyen P, Thind SK, Kurdgelashvili G,
Williams RJ. Characteristics and outcomes of US Veterans
at least 65 years of age at high risk of severe SARS-CoV-2
infection with or without receipt of oral antiviral agents. J
Infect [Internet]. 2023;86(3):248–55. Available from:
http://dx.doi.org/10.1016/j.jinf.2023.01.018
7 Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao
W, Wisemandle W, et al. Oral nirmatrelvir for high-risk,
nonhospitalized adults with covid-19. N Engl J Med
[Internet]. 2022;386(15):1397–408. Available from:
http://dx.doi.org/10.1056/nejmoa2118542
8 Kaizer AM, Shapiro NI, Wild J, Brown SM, Cwik BJ, Hart
KW, et al. Lopinavir/ritonavir for treatment of nonhospitalized patients with COVID-19: a randomized
clinical trial. Int J Infect Dis [Internet]. 2023;128:223–9.
Available from:
http://dx.doi.org/10.1016/j.ijid.2022.12.028
9 Keitel V, RES-Q-HR Trial Team, Jensen B, Feldt T, Fischer
JC, Bode JG, et al. Reconvalescent plasma/camostat
mesylate in early SARS-CoV-2 Q-PCR positive high-risk
individuals (RES-Q-HR): a structured summary of a study
protocol for a randomized controlled trial. Trials
[Internet]. 2021;22(1). Available from:
http://dx.doi.org/10.1186/s13063-021-05181-0
10 Lakatos B, Kowalska J, Antoniak S, Gokengin D,
Begovac J, Vassilenko A, et al. Retrospective evaluation of
an observational cohort by the Central and Eastern
Europe Network Group shows a high frequency of
potential drug–drug interactions among HIV‑positive
patients receiving treatment for coronavirus disease 2019
(COVID‑19). HIV Med [Internet]. 2022;23(6):693–700.
Available from: http://dx.doi.org/10.1111/hiv.13214
11 McCarthy MW. VV116 as a potential treatment for
COVID-19. Expert Opin Pharmacother [Internet]. 2023
[cited 2023 Nov 9];675–8. Available from:
https://pesquisa.bvsalud.org/global-literature-on-novelcoronavirus-2019-ncov/resource/ru/covidwho-2271505
12 McEvoy NL, Clarke JL, Mc Elvaney OJ, Mc Elvaney OF,
Boland F, Hyland D, et al. A randomised, double-blind,
placebo-controlled, pilot trial of intravenous plasma
purified alpha-1 antitrypsin for SARS-CoV-2-induced
Acute Respiratory Distress Syndrome: a structured
summary of a study protocol for a randomised, controlled
trial. Trials [Internet]. 2021;22(1):288. Available from:
http://dx.doi.org/10.1186/s13063-021-05254-0
13 Olagunju A, Fowotade A, Olagunoye A, Ojo TO, Adefuye
BO, Fagbamigbe AF, et al. Efficacy and safety of
nitazoxanide plus atazanavir/ritonavir for the treatment
of moderate to severe COVID-19 (NACOVID): A structured
summary of a study protocol for a randomised controlled
trial. Trials [Internet]. 2021;22(1). Available from:
http://dx.doi.org/10.1186/s13063-020-04987-8
14 Palanques-Pastor T, Megías-Vericat JE, Martínez P,
López Lorenzo JL, Cornago Navascués J, Rodriguez Macias
G, et al. Characteristics, clinical outcomes, and risk factors
of SARS-COV-2 infection in adult acute myeloid leukemia
patients: experience of the PETHEMA group. Leuk
Lymphoma [Internet]. 2021;62(12):2928–38. Available
from:
http://dx.doi.org/10.1080/10428194.2021.1948031
15 Panda PK, Bandyopadhyay A, Singh BC, Moirangthem
B, Chikara G, Saha S, et al. Safety and efficacy of antiviral
combination therapy in symptomatic patients of Covid-19
infection – a randomised controlled trial (SEV-COVID
Trial): A structured summary of a study protocol for a
randomized controlled trial. Trials [Internet]. 2020;21(1).
Available from: http://dx.doi.org/10.1186/s13063-020-
04774-5
16 Quinn TM, Gaughan EE, Bruce A, Antonelli J, O’Connor
R, Li F, et al. Randomised controlled trial of intravenous
nafamostat mesylate in COVID pneumonitis: Phase 1b/2a
experimental study to investigate safety,
Pharmacokinetics and Pharmacodynamics. EBioMedicine
[Internet]. 2022;76(103856):103856. Available from:
http://dx.doi.org/10.1016/j.ebiom.2022.103856
17 Santos CS, Morales CM, Álvarez ED, Castro CÁ, Robles
AL, Sandoval TP. Determinants of COVID-19 disease
severity in patients with underlying rheumatic disease.
Clin Rheumatol [Internet]. 2020;39(9):2789–96. Available
from: http://dx.doi.org/10.1007/s10067-020-05301-2
18 Singh RSP, Toussi SS, Hackman F, Chan PL, Rao R, Allen
R, et al. Innovative randomized phase I study and dosing
144
regimen selection to accelerate and inform pivotal
COVID‑19 trial of nirmatrelvir. Clin Pharmacol Ther
[Internet]. 2022;112(1):101–11. Available from:
http://dx.doi.org/10.1002/cpt.2603
19 Vicenzi M, Di Cosola R, Ruscica M, Ratti A, Rota I, Rota
F, et al. The liaison between respiratory failure and high
blood pressure: evidence from COVID-19 patients. Eur
Respir J [Internet]. 2020;56(1):2001157. Available from:
http://dx.doi.org/10.1183/13993003.01157-2020
20 WHO supports scientifically-proven traditional
medicine [Internet]. WHO | Regional Office for Africa.
[cited 2023 Nov 9]. Available from:
https://www.afro.who.int/news/who-supportsscientifically-proven-traditionalmedicine?gclid=Cj0KCQiAo7KqBhDhARIsAKhZ4ugZu0jM
UwYlndZXcXmh7HTb_2l2LsB1qr18r8Jp6pVm27wFvddjRUaApkKEALw_wcB
21 Xu Z, Shi D, Han J-B, Ling Y, Jiang X, Lu X, et al.
Preventive and therapeutic benefits of nelfinavir in
rhesus macaques and human beings infected with SARSCoV-2. Signal Transduct Target Ther [Internet].
2023;8(1). Available from:
http://dx.doi.org/10.1038/s41392-023-01429-0
22 Robinson P, Toussi SS, Aggarwal S, Bergman A, Zhu T,
Hackman F, et al. Safety, tolerability, and
pharmacokinetics of single and multiple ascending
intravenous infusions of PF-07304814 (lufotrelvir) in
participants hospitalized with COVID-19. Open Forum
Infect Dis [Internet]. 2023;10(8). Available from:
http://dx.doi.org/10.1093/ofid/ofad355
23 Mótyán JA, Mahdi M, Hoffka G, Tőzsér J. Potential
resistance of SARS-CoV-2 main protease (Mpro) against
protease inhibitors: Lessons learned from HIV-1 protease.
Int J Mol Sci [Internet]. 2022;23(7):3507. Available from:
http://dx.doi.org/10.3390/ijms23073507
24 King NM, Prabu-Jeyabalan M, Nalivaika EA,
Schiffer CA. Combating susceptibility to drug resistance.
Chem Biol [Internet]. 2004;11(10):1333–8. Available
from: http://dx.doi.org/10.1016/j.chembiol.2004.08.010
25 Da Cunha T, Wu GY, Vaziri H. Immunotherapyinduced hepatotoxicity: A review. J Clin Transl Hepatol
[Internet]. 2022;000(000):000–000. Available from:
http://dx.doi.org/10.14218/jcth.2022.00105
26 Cho YA, Han JM, Kang SY, Kim DC, Youn YJ, Choi
KH, et al. Analysis of risk factors for hepatotoxicity
induced by immune checkpoint inhibitors. J Immunother
[Internet]. 2021;44(1):16–21. Available from:
http://dx.doi.org/10.1097/cji.0000000000000347