Three protesters died in Jaleshwor of Mahottarai district in southern Nepal when police fired shots and teargas at them when they surrounded the police headquarters and torched the house of a local judge, said Home Ministry spokesperson Laxmi Prasad Dhakal.
Another agitator was seriously injured in the firing.
Clashes also broke out in the southern Saptari district, where one more protester was killed. The clashes erupted when protesters threw stones and bottles as police tried to escort vehicles through a blocked national highway.
Violent protests by Madhesis against the proposed charter have rocked the streets in southern plains.
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The disgruntled Madhes-based parties, representing the interests of the people of Terai region, want the drafting process to be halted immediately.
The Joint Madhesi Front has enforced a generel strike for the past 25 days and most of the schools, colleges, markets have remained closed, hitting the country's economy hard.
Private and public transport remained suspended in many districts of southern Nepal as the country tried to crawl back following the devastating earthquake in April, that killed more than 9,800 people.
The agitators, who claim their interests have been ignored in the new charter, have intensified their stir even as major political parties formally moved forward on the constitution drafting process despite a boycott by the Madhesi parties.
The protesters demand the seven-province model be scrapped and that they be given more representation and rights in the proposed charter.
So far 32 people, including eight policemen, have died in the violence over the past one month.